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Comparison of Bedtime Insulin Regimens in Patients with Type 2 Diabetes Mellitus: A Randomized, Controlled Trial

Hannele Yki-Järvinen, MD; Leena Ryysy, MD; Kati Nikkilä, MD; Timo Tulokas, MD; Raimo Vanamo, MD; and Marjatta Heikkilä, RN
[+] Article and Author Information

From University of Helsinki, Helsinki; Kymenlaakso Central Hospital, Kotka; Jorvi Hospital and Orion, Espoo; Lapland Central Hospital, Rovaniemi; and South Carelian Central Hospital, Lappeenranta, Finland.


Ann Intern Med. 1999;130(5):389-396. doi:10.7326/0003-4819-130-5-199903020-00002
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Background: Compared with other insulin regimens, combination therapy with oral hypoglycemic agents and bedtime insulin produces similar improvement in glycemic control but induces less weight gain.

Objective: To determine whether bedtime insulin regimens differ with respect to their effects on weight gain in patients with type 2 diabetes.

Design: Randomized, controlled trial.

Setting: Four outpatient clinics at central hospitals.

Patients: 96 patients (mean age, 58 ± 1 years; mean body mass index, 29 ± 1 kg/m2) whose type 2 diabetes was poorly controlled with sulfonylurea therapy (mean glycosylated hemoglobin value, 9.9% ± 0.2%; mean fasting plasma glucose level, 11.9 ± 0.3 mmol/L [214 ± 5 mg/dL]).

Intervention: Random assignment to 1 year of treatment with bedtime intermediate-acting insulin plus glyburide (10.5 mg) and placebo, metformin (2 g) and placebo, glyburide and metformin, or a second injection of intermediate-acting insulin in the morning. Patients were taught to adjust the bedtime insulin dose on the basis of fasting glucose measurements.

Measurements: Body weight, biochemical and symptomatic hypoglycemias, and indices of glycemic control.

Results: At 1 year, body weight remained unchanged in patients receiving bedtime insulin plus metformin (mean change, 0.9 ± 1.2 kg; P < 0.001 compared with all other groups) but increased by 3.9 ± 0.7 kg, 3.6 ± 1.2 kg, and 4.6 ± 1.0 kg in patients receiving bedtime insulin plus glyburide, those receiving bedtime insulin plus both oral drugs, and those receiving bedtime and morning insulin, respectively. The greatest decrease in the glycosylated hemoglobin value was observed in the bedtime insulin and metformin group (from 9.7% ± 0.4% to 7.2% ± 0.2% [difference, −2.5 ± 0.4 percentage points] at 1 year; P < 0.001 compared with 0 months and P < 0.05 compared with other groups). This group also had significantly fewer symptomatic and biochemical cases of hypoglycemia (P < 0.05) than the other groups.

Conclusions: Combination therapy with bedtime insulin plus metformin prevents weight gain. This regimen also seems superior to other bedtime insulin regimens with respect to improvement in glycemic control and frequency of hypoglycemia.

Figures

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Figure 1.
Change in body weight (top left), bedtime insulin dose (bottom left), glycosylated hemoglobin value (top right), and change in the glycosylated hemoglobin value (bottom right) during 12 months of insulin treatment in patients receiving bedtime insulin plus metformin (black circles), those receiving bedtime insulin plus glyburide (squares), those receiving bedtime insulin plus both oral agents (white circles), and those receiving bedtime and morning insulin (triangles).

In the top left and bottom left panels, x = < 0.05, xx = < 0.01, and xxx = < 0.01 for bedtime insulin plus metformin compared with all other treatments; in the top right and bottom right panels, xx = < 0.05 and xx = < 0.01 for bedtime insulin plus metformin compared with bedtime and morning insulin and bedtime insulin plus glyburide. In the top right and bottom right panels, * = < 0.05 and ** = < 0.01 for bedtime insulin plus glyburide and metformin compared with bedtime and morning insulin.

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Figure 2.
Relation between the mean annual fasting glucose level and the mean annual glycosylated hemoglobin value (top) and the frequency of biochemical hypoglycemias (bottom) (fasting glucose < 3.5 mmol/L [63 mg/dL]) in patients with type 2 diabetes.

The regression equation relating fasting glucose and glycosylated hemoglobin was as follows: glycosylated hemoglobin = 4.4 [95% CI, 3.3 to 5.5] + 0.50 [CI, 0.34 to 0.66] × fasting plasma glucose level [measured in mmol/L]. The gray area in the top panel indicates the normal range of glycosylated hemoglobin values. The dotted lines indicate glycosylated hemoglobin values that correspond to fasting glucose levels of 3 and 6 mmol/L (54 and 108 mg/dL).

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Figure 3.
Frequency (percentage of all measurements at a given time point) of biochemical hypoglycemias (blood glucose level < 3.5 mmol/L [63 mg/dL]) during home glucose monitoring of diurnal glucose profiles.PPPP

These frequencies differed significantly among the groups before lunch (2.7% of 648 measurements before lunch in patients receiving bedtime insulin plus glyburide and metformin compared with 0% in patients receiving bedtime insulin plus metformin [*** < 0.001] and 0.1% in patients receiving bedtime insulin plus glyburide [*** < 0.001]) and at 4 a.m. (4.7% of 603 measurements at 4 a.m. in patients receiving bedtime insulin plus glyburide compared with 2.2% in patients receiving bedtime and morning insulin; * < 0.05). The frequency of hypoglycemia was also higher before lunch in the bedtime and morning insulin groups than in the bedtime insulin and glyburide or metformin groups (** < 0.01). B = breakfast; D = dinner; L = lunch.

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