Good Glycemic Control With Flexibility in Timing of Basal Insulin Supply : A 24-week comparison of insulin glargine given once daily in the morning or at bedtime in combination with morning glimepiride

The study objective was to compare the frequency of nocturnal hypoglycemia following morning or bedtime administration of glargine plus glimepiride. In a multinational, open-label, randomized study, 624 patients with type 2 diabetes poorly controlled on oral agents received morning or bedtime glargine plus morning glimepiride (2, 3, or 4 mg) for 24 weeks titrated to target FBG ≤100 mg/dl. Patient demographics and baseline characteristics were similar across the two treatment arms (aged 62.1 vs. 61.5 years, BMI 28.2 vs. 28.7 kg/m², and diabetes duration 9.5 vs. 10.3 years). The primary outcome, incidence of nocturnal hypoglycemia (hypoglycemia while the patient was asleep, after the evening injection and before rising), was compared using one-sided 95% CIs.

The frequency of nocturnal hypoglycemia was equivalent between the groups, with morning glargine noninferior to bedtime (13.0 vs. 14.9%, 95% CI −100 to 2.84%). Most patients who experienced nocturnal hypoglycemia had only one episode (51.3 vs. 54.8%).

At end point, clinically meaningful reductions in HbA_1c were observed in both groups: −1.7 ± 1.2%, from 8.8 ± 1.0 to 7.2 ± 1.1% (morning) and −1.6 ± 1.2%, from 8.8 ± 1.0 to 7.2 ± 1.1% (bedtime). A reduction in FBG also occurred: −76.55 ± 50.76 (morning) vs. −80.69 ± 49.41 mg/dl (bedtime) (P = 0.08), with no significant differences in hypoglycemia. The proportion of patients with HbA_1c ≤7.0% was comparable for the two treatment groups (P = 0.66), with 48% (n = 149) and 47% (n = 143) of patients achieving HbA_1c ≤ 7.0% at end point in the morning and bedtime groups, respectively. Baseline to end point decreases in nocturnal and mean daily blood glucose were similar in both groups (nocturnal blood glucose: −68.64 ± 58.53 vs. −70.10 ± 56.72 mg/dl, P = 0.52; mean daily blood glucose: −73.42 ± 56.55 vs. −68.35 ± 54.45 mg/dl, P = 0.13; all morning versus bedtime). Mean daily insulin dose at end point was comparable between the groups (34.7 ± 17.4 vs. 32.4 ± 17.0 IU, P = 0.15).

Treatment-emergent adverse events were observed in 308 patients, with no clinically relevant between-treatment differences. Possible treatment-related treatment-emergent adverse events occurred in 3.5% of patients (morning: 2.9%; bedtime: 4.1%); 8.0% experienced severe treatment-emergent adverse events (morning: 8.8%; bedtime: 7.3%).

In conclusion, glargine, due to its 24-h action and flat profile, is an appropriate and flexible add-on therapy to start insulin treatment in patients with type 2 diabetes. Flexible dosing with simple glimepiride/glargine regimens achieved significant and practically meaningful improvements in glycemic control, regardless of administration time and without differences in hypoglycemia. This flexibility should facilitate initiation of and adherence to insulin therapy and thus lead to improvements in glycemic control.

This study was supported by a research grant from Aventis Pharma.

Data from the manuscript have been published in abstract form [Diabetes 52 (Suppl. 1):A134, 2003; Diabetologia 46 (Suppl. 2):A6, 2003] and presented as posters at the American Diabetes Association 2003 and European Association for the Study of Diabetes 2004 congresses and orally at the International Diabetes Federation 2003 congress.