Similar Risk of Congenital Defects With Detemir Versus Other Basal Insulins

Long-acting insulins like detemir and other basal insulins like insulin glargine carry a similar risk of major congenital malformations, perinatal or neonatal death, and maternal conditions like hypoglycemia, preeclampsia, and stillbirth, according to research results published in Diabetes Care.

In the EValutaion Of LeVEmir in Pregnancy Study (EVOLVE) (ClinicalTrials.gov Identifier NCT01892319), researchers sought to evaluate the potential role that detemir vs other basal insulins play in the risk of having offspring with either major congenital malformations, perinatal, or neonatal death. Researchers also evaluated glycated hemoglobin levels (HbA_1c) during pregnancy and the incidence of major hypoglycemia and preeclampsia. Pregnant women with preexisting diabetes are at an increased risk of adverse maternal and fetal outcomes, including stillbirth, if their diabetes is not well controlled.

EVOLVE was a large, multinational, prospective, noninterventional, multicenter study of pregnant women with preexisting type 1 or type 2 diabetes to evaluate the safety of detemir vs other basal insulins in pregnancy. Women in early pregnancy from 92 sites in 17 countries were enrolled. The study began in September 2013 and ended in September of 2019 and was sponsored by Novo Nordisk A/S, the makers of Levemir®, which is the brand name of detemir.

The primary endpoint of the clinical trial was a composite of the proportion of pregnancies completing ≥22-weeks gestation in detemir-treated women vs women treated with other basal insulins, who did not experience major congenital malformations, perinatal death, or neonatal death in their fetuses.

A total of 2373 pregnant women met inclusion criteria for the study, 1457 of whom were receiving basal insulin at enrollment and were treated with unchanged basal insulin during early pregnancy. Women who changed their type of basal insulin during pregnancy (n=135) or who were not receiving basal insulin at enrollment, likely due to pump treatment (n=781) were excluded from the analysis, leaving a total of 727 women using insulin detemir and 730 using other basal insulins in the study group.

A total of 1456 mothers were pregnant with 1431 singletons and 25 twin pairs for a total of 1481 fetuses. In the detemir group, mothers were pregnant with 713 singletons and 14 twin pairs, while women using other basal insulins  were pregnant with 718 singletons and 11 twin pairs. Of the 1481 total fetuses, 1360 were born at 22 gestational weeks or older; 1345 were born alive.

Baseline between-group characteristics were comparable. Most study participants  had type 1 diabetes (81.8% in the detemir group vs 89.6% in the basal insulin group), and fewer women (63.9%) in the detemir group had folic acid supplementation either before or during the first trimester vs 80.1% in the basal group.

Unadjusted prevalence of newborns without major congenital malformations or perinatal or neonatal death was similar between groups: 97.0% in the detemir group vs 95.5% in the  basal insulin groups (crude risk difference, 0.015; 95% CI, -0.01 to 0.04; adjusted risk difference, -0.003; 95% CI, -0.03 to 0.03).

In the detemir group, the crude prevalence of a fetus with at least 1 major or minor congenital malformation was lower with detemir vs other basal insulins—9.4% vs 12.6%—which was similar for the prevalence of at least 1 major congenital fetal malformation (2.7% vs 3.8%) or at least 1 minor malformation (6.7% vs 8.7%).

In total, 20 fetuses in the detemir group had at least 1 major congenital malformation vs 28 in the other basal insulins group. The most common malformations were related to the cardiovascular system (10 vs 9, respectively), the genitourinary system (4 vs 9) and the nervous system (7 vs 8). Forty-nine fetuses in the detemir group also had at least 1 minor—but not major—congenital malformation (vs 64 in the other basal group), which included malformations related to the cardiovascular and genitourinary systems.

Crude prevalence of perinatal death was lower in the detemir vs other basal insulins group (0.9% vs 1.9%); rates were similar for stillbirth and induced abortion of fetuses with major congenital malformations. While the difference in stillbirth was significant prior to adjustment, the differences were not significant for any variables after adjusting for confounders.

Estimated mean maternal HbA_1c levels decreased gradually from conception to the end of the first and second trimesters (detemir: 7.3% to 6.5% to 6.1%; basal: 7.5% to 6.7% to 6.3%); levels rose slightly at the end of the third trimester (6.3% vs 6.4%), respectively. The crude estimated mean difference was significant at the end of the first and second trimesters (-0.181 and -0.139). No significant differences were noted after adjusting for confounders.

Results of a crude analysis indicated significantly lower risks of major hypoglycemia and preeclampsia in the detemir group compared with other basal insulins (6% vs 9% and 6.4% vs 10%, respectively).

Study limitations, according to the authors of the report, “included the fact that real-life studies are not as strictly controlled as randomized control trials (RCT)”,  the recruitment of women at specialized diabetes sites (which may affect the ability to generalize results), and the potential that some rare events were missed that may have resulted in relatively low stastical power for some endpoints, as well as the reduction in the number of women and fetuses analyzed after propensity score matching. Additionally, the study authors noted that women are often advised to take folic acid supplements prior to conception and in early pregnancy, but they felt this was an unlikely to be a contributor to the lower number of congenital malformations seen among women using insulin detemir since the intake of folic acid was reported to be less frequent in that group.

“Treatment with insulin detemir was associated with a comparable risk to other basal insulins of major congenital malformations, perinatal or neonatal death, hypoglycemia, preeclampsia, and stillbirth,” the researchers concluded, while noting  “even larger studies are needed to make firm conclusions.”

Disclosure: This clinical trial was supported by Novo Nordisk. Please see the original reference for a full list of authors’ disclosures.

Reference

Mathisen ER, Ali N, Alibegovic AC, Anastasiou E, et al. Risk of major congenital malformations or perinatal or neonatal death with insulin detemir versus other basal insulins in pregnant women with preexisting diabetes: the real-world EVOLVE Study. Diabetes Care. 2021;44(9):2069-2077. doi: 10.2337/dc21-0472