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Ann Intern Med. 2002 Apr 2;136(7):504-14.

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.

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  • 1Department of Internal Medicine, University of Perugia, Via E. Dal Pozzo, I-06126 Perugia, Italy.



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


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


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


University research center in Italy.


22 C-peptide-negative persons with type 1 diabetes mellitus (mean age [+/-SD], 29 +/- 3 years).


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.


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


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.


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.

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