Maternal glycaemic control and hypoglycaemia in pregnancy: a randomised trial comparing insulin detemir with NPH insulin in 310 subjects with type 1 diabetes

Background and aims: Rigorous data investigating basal insulin analogues in diabetic pregnancy are lacking. The aim of this prospective, randomised, controlled, parallel-group, open-label trial was to compare the efficacy and safety of insulin detemir (IDet) vs. NPH (both with prandial insulin aspart) in pregnant women with type 1 diabetes (T1DM). Materials and methods: T1DM women (HbA1c ≤8 % at pregnancy confirmation) were randomised to IDet (n=152) or NPH (n=158) up to 12 months before pregnancy or during pregnancy at 8-12 weeks gestation. The primary objective was to show that IDet was non-inferior to NPH for HbA1c at 36 gestational weeks (GWs) (primary endpoint). Non-inferiority was shown if the upper limit of the 95% CI for the treatment difference of IDet vs. NPH was below the pre-specified non- inferiority margin of 0.4% for both the Full Analysis Set (FAS) and Per Protocol Set (PP). The data were analysed using linear regression with effects of treatment, country and pregnancy status at randomisation, HbA1c at randomisation and the HbA1c at randomisation by pregnancy status at randomisation interaction. Results: 79 and 83 women in the IDet and NPH groups, respectively, were pregnant at randomisation while 73 and 75 women, respectively, became pregnant following randomisation. Mean±SD demographics were: age 30.1±4.4 yrs ; BMI 24.8±4.1 kg/m2 ; HbA1c 7.01±0.79% ; fasting plasma glucose (FPG) 5.94±3.25 mmol/l and diabetes duration 12.3±8.0 yrs. For FAS, the estimated HbA1c at GW36 was 6.27% for IDet and 6.33% for NPH. IDet was shown to be non- inferior to NPH and not superior (FAS: -0.06, 95% CI: -0.21 ; 0.08 ; PP: -0.151 ; 95% CI: -0.34 ; 0.04). Patients reaching HbA1c ≤6.0% at both GW 24 + 36 was higher with IDet (36%) vs. NPH (29%), p=NS. Estimated FPG was significantly lower with IDet vs. NPH at GW 24 (5.38 vs. 6.32 mmol/l, difference -0.94 [-1.67 ; -0.21], p=0.012) and at GW 36 (4.76 vs. 5.41 mmol/l, difference -0.65 [-1.19 ; -0.12], p=0.017). There were no statistically significant or clinically relevant differences in hypoglycaemic events between treatments. The rate of major hypoglycaemia (events/yr) was 1.1 for IDet vs. 1.2 for NPH. There was no difference between groups in weight gain during pregnancy (11.5 kg and 11.0 kg, respectively). Mean doses of basal and bolus insulin increased during the 2nd and 3rd trimester and decreased after pregnancy, with no differences between treatments. Conclusion: Lower FPG, but comparable HbA1c in late pregnancy was obtained using insulin detemir in comparison to NPH insulin in women with type 1 diabetes. Figure. Mean±SD HbA1c during pregnancy by timing of randomisation. D=delivery ; 6WPP=6-weeks postpartum.