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The addition of evening-NPH insulin to oral hypoglycemics reduced weight gain and hyperinsulinemia in patients with type 2 diabetes

ACP J Club. 1993 Mar-April;118:38. doi:10.7326/ACPJC-1993-118-2-038

Source Citation

Yki-Järvinen H, Kauppila M, Kujansuu E, et al. Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1992 Nov 12;327:1426-33.



To compare 4 insulin-treatment regimens with continued oral hypoglycemic drug therapy in patients with type 2 diabetes mellitus.


Randomized controlled trial with 3-month follow-up.


6 hospitals in Finland.


Patients (age range 40 to 70 y) with a stable body mass index (BMI) < 35 kg/m2, a fasting blood glucose level > 144 mg/dL, type 2 diabetes for > 3 years, on maximum-dose glipizide or glyburide alone or with metformin, and a fasting serum C-peptide level > 0.33 nmol/L. Exclusion criteria were previous heart disease or stroke, nephropathy, severe retinopathy, other serious illnesses, previous insulin therapy for > 2 weeks, excessive alcohol consumption, night work, serum triglyceride > 5 mmol/L, or presence of islet-cell antibodies. 153 patients (mean age 59 y, 81 women, mean BMI 28 kg/m2) were studied.


Patients were randomized to 5 groups: The morning-NPH group continued oral hypoglycemic (usual) therapy and received NPH insulin before breakfast; the evening-NPH group continued usual therapy and received NPH insulin at 2100 hours; the 2-insulin injection group discontinued usual therapy and took insulin (NPH and regular insulin in a ratio of 70:30 twice daily); the multiple-injection group had NPH insulin at 2100 hours and regular insulin before all meals; and control patients continued usual medications. Insulin was adjusted to maintain normoglycemia.

Main outcome measures

Diurnal blood glucose and insulin profiles were measured at baseline and 3 months. Patients were seen at 2 weeks and 1 and 2 months to review home glucose levels and episodes of hypoglycemia and to measure body weight and fasting blood glucose. Glycosylated hemoglobin (HbA1c), lipids, and well-being were also measured.

Main results

The mean HbA1c decreased in all 4 insulin groups (difference for all treatments vs. control group, 0.5%; P < 0.01). The evening-NPH group had the lowest weight gain (1.2 kg, P < 0.05 for the comparison with the multiple injection group) and lower diurnal serum-free insulin (50% to 65% less, P < 0.05 for comparisons with the 3 treatment groups). Subjective well-being was higher for all treatment groups compared with the control group (P < 0.001 for all comparisons). The treatment groups did not differ for symptomatic hypoglycemia, blood pressure, or serum cholesterol.


For patients with type 2 diabetes receiving oral hypoglycemics, the addition of evening-NPH insulin caused less weight gain and hyperinsulinemia than other regimens with comparable glycemic control.

Sources of funding: Finnish State Medical Research Council; Sigrid Juselius Foundation; Novo Nordisk.

For article reprint: Dr. H. Yki-Järvinen, Second Department of Medicine, Helsinki University, Haartmaninkatu 4, SF-00290 Helsinki, Finland. FAX 358-9-471-2250.


The role of combined insulin and sulfonylurea therapy in the treatment of type 2 diabetes has generated considerable controversy. The design of this well-planned study by Yki-Järvinen and colleagues sheds new light on the issue. First, unlike most earlier studies, the current study compared a variety of insulin regimens (with and without oral hypoglycemic therapy) with oral hypoglycemic therapy alone. Second, an aggressive attempt was made to achieve "good" glycemic control in all 4 treatment groups. Although there should be little disagreement about the statistical validity of the trial's results, controversy about the potential clinical advantages of the evening-NPH plus oral hypoglycemic regimen is likely to persist (1, 2). Yki-Järvinen and colleagues concluded that the evening-NPH regimen was the most favorable because hyperinsulinemia and weight gain were minimized. No confirmatory evidence exists, however, that peripheral insulin levels are causally related to vascular morbidity. Further, the differences in weight gain between the evening-NPH and other treatment groups were statistically significant but relatively small (< 2 kg).

Overall, the results suggest that the evening-NPH regimen is a reasonable alternative to other insulin regimens for the treatment of type 2 diabetes. Long-term trials with larger numbers of patients may determine whether the evening-NPH regimen maintains its effectiveness beyond 3 months and whether it is associated with an enhanced quality of life or reduction in diabetes-related morbidity compared with other regimens.

Paul D. Levinson, MD
Brown University School of MedicineProvidence, Rhode Island, USA


1. Raskin P. Combination therapy in NIDDM. N Engl J Med. 1992;327:1452-3.

2. Pugh JA, Wagner ML, Sawyer J, et al. Is combination sulfonylurea and insulin therapy useful in NIDDM patients? A meta-analysis. Diabetes Care. 1992;15: 953-9.