Administration of Neutral Protamine Hagedorn Insulin at Bedtime versus with Dinner in Type 1 Diabetes Mellitus To Avoid Nocturnal Hypoglycemia and Improve Control

A Randomized, Controlled Trial

  1. Carmine G. Fanelli, MD, PhD;
  2. Simone Pampanelli, MD;
  3. Francesca Porcellati, MD, PhD;
  4. Paolo Rossetti, MD;
  5. Paolo Brunetti, MD; and
  6. Geremia B. Bolli, MD
  1. From University of Perugia, Perugia, Italy.

    Abstract

    Background: Intensive insulin treatment of type 1 diabetes mellitus increases the risk for nocturnal hypoglycemia.

    Objective: To demonstrate that splitting the evening insulin regimen reduces the risk for nocturnal hypoglycemia in intensive treatment of type 1 diabetes mellitus.

    Design: Randomized, open, two-treatment crossover trial in two 4-month periods.

    Setting: University research center in Italy.

    Patients: 22 C-peptide–negative persons with type 1 diabetes mellitus (mean age [±SD], 29 ± 3 years).

    Interventions: Each patient was randomly assigned to one of two insulin regimens for 4 months and then switched to the other regimen for another 4 months. The two treatment regimens were 1) mixed treatment—a mixture of human regular and neutral protamine Hagedorn [NPH] insulin administered before dinner and 2) split treatment—human regular insulin administered at dinner and NPH insulin administered at bedtime.

    Measurements: Frequency of nocturnal hypoglycemia. Secondary end points were levels of fasting blood glucose and hemoglobin A1c and responses to experimental hypoglycemia.

    Results: During the split-regimen treatment period, patients had fewer episodes of nocturnal hypoglycemia (mean [±SE], 0.10 ± 0.02 episode/patient-day vs. 0.28 ± 0.04 episode/patient-day; P = 0.002), a lower fasting blood glucose level (mean [±SE], 7.6 ± 0.2 mmol/L vs. 8.3 ± 0.5 mmol/L [137 ± 4 mg/dL vs. 160 ± 8 mg/dL]; P = 0.030), less variable fasting blood glucose levels (SD range, 2.0 ± 0.4 vs. 3.5 ± 0.6; P = 0.001), and lower hemoglobin A1c value (mean [±SE], 7.0% ± 0.11% vs. 7.5% ± 0.15%; P = 0.004) than during the mixed regimen. Responses to experimental hypoglycemia were better preserved with the split regimen than with the mixed regimen.

    Conclusion: When the goal of insulin therapy in type 1 diabetes mellitus is near-normoglycemia, splitting the evening insulin treatment regimen into short-acting insulin at dinner and NPH insulin at bedtime reduces the risks for nocturnal hypoglycemia and hypoglycemia unawareness and decreases the hemoglobin A1c value compared with mixing short-acting insulin and NPH insulin at dinner.

    Article and Author Information

    • Acknowledgments: The authors thank Mad Judge Stout in Falkland Arms, Great Tew, United Kingdom, for his support.

    • Grant Support: By Juvenile Diabetes Research Foundation International (grant 1-2001-102).

    • Requests for Single Reprints: Geremia B. Bolli, MD, Department of Internal Medicine, University of Perugia, Via E. Dal Pozzo, I-06126 Perugia, Italy; e-mail, gbolli{at}dimisem.med.unipg.it.

    • Current Author Addresses: Drs. Fanelli, Pampanelli, Porcellati, Rossetti, Brunetti, and Bolli: Department of Internal Medicine, University of Perugia, Via E. Dal Pozzo, I-06126 Perugia, Italy.

    • Author Contributions: Conception and design: C.G. Fanelli, S. Pampanelli, F. Porcellati, P. Rossetti, P. Brunetti, G.B. Bolli.

    • Analysis and interpretation of the data: C.G. Fanelli, S. Pampanelli, F. Porcellati, P. Brunetti, G.B. Bolli.

    • Drafting of the article: C.G. Fanelli, S. Pampanelli, F. Porcellati, G.B. Bolli.

    • Critical revision of the article for important intellectual content: C.G. Fanelli, S. Pampanelli, F. Porcellati, P. Brunetti, G.B. Bolli.

    • Final approval of the article: C.G. Fanelli, S. Pampanelli, F. Porcellati, P. Rossetti, P. Brunetti, G.B. Bolli.

    • Provision of study materials or patients: S. Pampanelli, F. Porcellati, P. Rossetti, G.B. Bolli.

    • Statistical expertise: C.G. Fanelli, G.B. Bolli.

    • Obtaining of funding: C.G. Fanelli, F. Porcellati, P. Brunetti, G.B. Bolli.

    • Administrative, technical, or logistic support: P. Brunetti.

    • Collection and assembly of data: C.G. Fanelli, S. Pampanelli, P. Rossetti.

    Summary for Patients

    • Summaries for Patients:Splitting the Evening Insulin Dose To Avoid Low Blood Sugar Levels and To Improve Sugar Control in Patients with Type 1 Diabetes Ann Intern Med April 2, 2002 136:I29
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    1. Ann Intern Med April 2, 2002 vol. 136 no. 7 504-514
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