Current issues of ACP Journal Club are published in Annals of Internal Medicine


A split regimen of regular insulin at dinner and NPH insulin at bedtime reduced nocturnal hypoglycemia in type 1 diabetes


ACP J Club. 2002 Nov-Dec;137:89. doi:10.7326/ACPJC-2002-137-3-089

Source Citation

Fanelli CG, Pampanelli S, Porcellati F, et al. 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. Ann Intern Med. 2002 Apr 2;136:504-14. [PubMed ID: 11926785] (All 2002 articles were reviewed for relevancy, and abstracts were last revised in 2008.)



In patients with type 1 diabetes mellitus receiving intensive treatment with injections of regular insulin before meals, is the administration of regular insulin with the evening meal and neutral protamine Hagedorn (NPH) insulin at bedtime (split regimen) more effective than administering both with the evening meal (mixed regimen) for reducing nocturnal hypoglycemia?


8-month randomized {allocation concealed*}†, unblinded,* crossover trial.


An outpatient diabetes clinic at a university hospital in Perugia, Italy.


22 patients (mean age 29 y, 55% men) who had type 1 diabetes; were receiving long-term intensive insulin treatment; had no retinopathy, neuropathy, nephropathy, or hypertension; and were taking no medications other than insulin. Patients were excluded if they had hypoglycemia unawareness (absence of symptoms and a blood glucose level of 2.5 to 2.8 mmol/L) or episodes of hypoglycemia requiring assistance in the previous year. Follow-up was complete.


For a 1-month run-in period, patients used the split regimen and were then allocated to continue with the split regimen or to begin the mixed regimen for 4 months, after which they were switched to the other treatment for another 4 months. Insulin was administered to achieve fasting blood glucose values of 5.0 to 6.7 mmol/L before meals and at bedtime.

Main outcome measures

Nocturnal hypoglycemia, and fasting-blood glucose and hemoglobin A1c levels. Patient data from the last month of each treatment period were used for the analysis.

Main results

When receiving the split regimen, patients had fewer episodes of hypoglycemia at 3:00 a.m., a mean of 2.8 (95% CI 1.9 to 3.7) fewer episodes of hypoglycemia, and lower fasting blood glucose and HbA1c levels than when they received the mixed regimen (Table).


In patients with type 1 diabetes mellitus receiving intensive treatment, administration of regular insulin before each meal and neutral protamine Hagedorn (NPH) insulin at bedtime reduced nocturnal hypoglycemia and improved control of blood glucose levels more than mixing the evening dose of regular insulin with NPH and administering this mix with the evening meal.

*See Glossary.

†Information provided by author.

Source of funding: Juvenile Diabetes Research Foundation International.

For correspondence: Dr. G.B. Bolli, University of Perugia, Perugia, Italy. E-mail

Table. Split vs mixed evening insulin regimen for type 1 diabetes at 8 months‡

Outcomes Split Mixed P value or mean difference (95% CI)
Episodes of hypoglycemia at 3:00 a.m. per patient-d 0.10 0.28 0.18 (0.07 to 0.27)
Fasting blood glucose level (mmol/L) 7.6 8.9 0.030
Hemoglobin A1c level (%) 7.0 7.5 0.5 (0.18 to 0.81)

‡Values are means from the last month of each treatment period. All comparisons favor the split-insulin regimen.


Near-normal glycemia (achieved by using multiple daily insulin injections [MDI] or an insulin pump) decreases retinopathy in type 1 diabetic patients with no or early retinopathy (1) but increases the risk for hypoglycemia (mostly nocturnal) by at least 3-fold (2).

Because hypoglycemia adversely affects quality of life and glycemic control, clinicians and patients value randomized trials of insulin regimens that reduce nocturnal hypoglycemia. The study by Fanelli and colleagues showed that administration of NPH insulin at bedtime rather than with the evening meal decreased the risk for nocturnal hypoglycemia by 60%.

The investigators were not blind to allocation, an issue that would require an innovative design. The applicability of the study findings is limited by the otherwise-understandable exclusion of patients with hypoglycemic unawareness, a group particularly vulnerable to hypoglycemia.

Other investigators have successfully decreased nocturnal hypoglycemia by replacing human insulin in MDI regimens with insulin analogues (insulin lispro or aspart and glargine insulin, which cannot be mixed) (3-5). Further research to make safer and more convenient MDI regimens is eagerly awaited, including comparisons of insulin glargine with ultralente insulin and inhaled insulin as bolus insulin.

Yogish C. Kudva, MD
Mayo Clinic
Rochester, Minnesota, USA


1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-86. [PubMed ID: 8366922]

2. The DCCT Research Group. Epidemiology of severe hypoglycemia in the diabetes control and complications trial. Am J Med. 1991;90:450-9. [PubMed ID: 2012085]

3. Heller SR, Amiel SA, Mansell P. Effect of the fast-acting insulin analog lispro on the risk of nocturnal hypoglycemia during intensified insulin therapy. U.K. Lispro Study Group. Diabetes Care. 1999;22:1607-11. [PubMed ID: 10526722]

4. Home PD, Lindholm A, Riis A. Insulin aspart vs. human insulin in the management of long term blood glucose control in type 1 diabetes mellitus: a randomized controlled trial. Diabet Med. 2000;17:762-70. [PubMed ID: 11131100]

5. Ratner RE, Hirsch IB, Neifing JL, et al. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. US study group of Insulin Glargine in Type 1 Diabetes. Diabetes Care. 2000;23:639-43. [PubMed ID: 10834423]