Comparison of treatment with insulin Detemir and NPH in women with gestational diabetes mellitus: glycemic control and pregnancy outcomes

Abstract

Purpose.

The objective of this retrospective study was to compare glycemic control, pregnancy outcome, as well as fetal/neonatal outcomes, between women with gestational diabetes mellitus (GDM) treated with (a) insulin detemir and (b) insulin neutral protamine Hagedorn (NPH).

Methods.

A total of 192 women with GDM were included. 98 women received detemir, while 94 women received NPH. Data regarding medical history, glycemic control, time and mode of delivery, as well as neonatal outcomes were recorded.

Results.

Baseline characteristics were comparable between the two groups. There were no differences with respect to the week of insulin initiation, total insulin dose, duration of insulin therapy, daily insulin dose/weight in early and late pregnancy, as well as the number of insulin injections per day. Maternal overall weight gain during pregnancy, and weight gain per week did not differ either. The detemir group had slightly lower HbA1c level at the end of gestation [median: Det 5.2% (33 mmol/mol) vs NPH 5.4% (36 mmol/mol), p = 0.035). There were no hypoglycemias or allergic reactions in both groups. There were also no differences regarding neonatal outcomes

Conclusion.

The use of insulin detemir for glucose control was found to be equally effective and safe compared with NPH.

Introduction

Hyperglycemia during pregnancy is associated with increased risk of fetal, neonatal and maternal outcomes that can be avoided by tight glycemic control. [1, 2] The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study has shown that there is a continuous association between the rise of maternal glucose levels and the risk of adverse pregnancy outcomes, including neonatal hypoglycemia and increased rate of macrosomia and cesarean section. [3] Several studies have demonstrated that in GDM these complications can be reduced by achieving better glycemic control. [4, 5] However, this still remains a challenging and sometimes unattainable goal. During pregnancy only human insulin was widely used until recently, but its use is now limited due to the risk of hypoglycemia. Better pharmacokinetic and pharmacodynamics profiles of insulin analogues may help overcome this obstacle.

In recent years, insulin detemir, a long-acting insulin analogue, has been increasingly studied for use in pregnancy. In 2012, insulin detemir received U.S. Food and Drug Administration approval for reclassification to pregnancy category B from pregnancy category C. This was based on the results of small observational studies and mostly of a randomized control trial (RCT) comparing insulin detemir and NPH in 310 pregnant women with Type 1 Diabetes Mellitus (T1DM). [6–9] This large prospective study found that insulin detemir was not inferior to NPH concerning glycemic control as well as maternal and neonatal outcomes. [8, 9]

Pharmacodynamics represent the main difference between the two types of insulin. NPH peaks between 4 and 12 hours after injection with a duration of action around 14 hours, while insulin detemir is characterized by a slower onset and a longer duration of action (18–20 hours) with no pronounced peak. [10, 11] NPH has been studied and used for several years in non-pregnant and pregnant patients with proven safety and efficacy. However, it cannot mimic the physiological profile of insulin release and has been associated with higher rates of maternal hypoglycemia. [12] On the other hand, detemir as insulin analog is more recent and less studied but it has a “peakless” activity with lower variability of action, and can lead to fewer hypoglycemic events. [13, 14]

However, the number of studies investigating GDM women on insulin detemir is limited. In a randomized controlled trial, 87 pregnant women with GDM or Type 2 Diabetes Mellitus (T2DM) insulin detemir (n = 42) or NPH (n = 45), with short-acting insulin aspart as needed. The primary outcome was overall mean blood glucose (BG) during insulin treatment. The trial found no difference in the primary outcome, the time it took to achieve good glycemic control, maternal weight gain, and perinatal/neonatal outcomes in both treatment arms. Hypoglycemic events were lower in the detemir group. [15] Another randomized trial by Ji et al compared the efficacy and safety of insulin detemir vs NPH in 132 women with pregestational diabetes and 108 with GDM and found that detemir could control blood glucose and reached the targets faster and more effectively, with lower incidence of maternal hypoglycemia and comparable adverse birth outcomes. [16] In a recent multinational prospective cohort study “The Real World EVOLVE Study” in pregnant women with pre-existing diabetes, insulin detemir was associated with a similar risk to other basal insulins of major congenital malformations perinatal or neonatal death, hypoglycemia, pre-eclampsia, and stillbirth. [17] Further, a meta-analysis of RCTs comparing insulin detemir versus NPH in 1450 pregnant women with gestational or pregestational diabetes showed significant results in favor of insulin detemir concerning maternal hypoglycemic events and gestational age at delivery. [18]

Notably, real life data concerning the use of insulin detemir alone in GDM is limited. The aim of this retrospective study was to compare glycemic control, pregnancy outcome, as well as fetal and neonatal outcomes between women with GDM treated with insulin detemir and insulin NPH.

Materials And Methods

Protocol

Pregnant women visited our clinic at approximately 2-week intervals. During every visit weight, HbA1c, blood pressure, fasting plasma glucose and 1-hour glucose after standard breakfast, as well as insulin dose were recorded. All women were recommended to follow a specific diet and to perform self-monitoring of plasma glucose values 4–6 times daily, specifically morning fasting, 1 hour after meals, before bedtime, and before main meals. The patients recorded their blood glucose values in diabetes diaries, which were evaluated at each visit. Insulin doses were adjusted to maintain good glycemic control according to treatment targets (fasting blood glucose < 90mg/dl (5 mmol/l), 1-hour postprandial blood glucose ≤ 130mg/dl (7.8 mmol/l). [20] Fetal ultrasound was performed on a routine basis at inclusion, at 13, 21, 32 weeks and when necessary.

Adverse events were also recorded (allergies and hypoglycemias). Major hypoglycemia was defined as an evenτ which a person was unable to treat on their own. Minor hypoglycemia was defined as an episode in which the subject was able to treat herself and had a blood glucose of < 56mg/dl (3.1 mmol/l). [8] Hypoglycemic episodes were recorded by the patients in their diaries. Pre-eclampsia was also recorded. Data regarding medical history, parameters of glycemic control, insulin type, insulin dose, number of injections, adverse events, time and mode of delivery and neonatal outcomes were identified from the medical records. Neonatal outcomes included any congenital malformation, preterm delivery (delivery < 37 completed weeks), early fetal death (< 22 completed weeks), perinatal death (death occurring between 22 completed weeks and one completed week after delivery), neonatal mortality (postpartum death after 7 completed days and before 28 completed days after delivery), 5-minute Apgar score < 7, neonatal hypoglycemia after delivery (plasma glucose < 45mg/dl (2.5 mmol/l)), neonatal jaundice, time of delivery, cesarean delivery, birth weight, birth weight adjusted for gestational age and live-born infants with a birth weight < 10th or > 90th percentile for gestational age and sex, according to local practice.

Results

Ultimately, as stated above, 192 pregnant women were included for evaluation: 98 were treated with insulin detemir and 94 with NPH during pregnancy. Patient demographics and baseline characteristics are shown in Table 1. The baseline characteristics, such as age, BMI before pregnancy, rates of smoking, hypertension, education level, ethnicity or family history of T2DM were comparable between both groups.

Maternal weight gain per week since the start of insulin until delivery, and overall, in pregnancy did not differ between the groups (Τable 2). There were no episodes of symptomatic hypoglycemias or allergic reactions in both groups. Further, no hypertensive disorders or pre-eclampsia were noted.

There were also no differences regarding the week of insulin initiation, as well as the duration of insulin therapy (Table 2). The median daily insulin dose (IU/kg) was comparable between the detemir and NPH groups both in the beginning of insulin treatment and at delivery (Table 2). In addition, there were no differences with respect to the number of insulin injections per day (given as a single bedtime injection in all cases).

Discussion

In our study we evaluated retrospectively the effectiveness and safety of insulin detemir versus NPH in 192 pregnant women with GDM. In this large cohort of pregnant women, the use of insulin detemir for glucose control was found to be equally effective compared with NPH, with a slightly lower HbA1c in the detemir group in late gestation. Furthermore, no differences were observed with respect to maternal adverse outcomes or neonatal complications.

The number of studies investigating insulin Detemir in pregnant women is limited and the majority of them refer to pregestational diabetes, T1DM or T2DM. [6–9, 15, 16, 17, 18, 20–24] The first published data concerning insulin detemir in diabetic pregnancy are those of the retrospective assessment of 10 Type 1 diabetic pregnant women by Lapolla et al in 2009 [6] and of 18 women (14 with Type 1 and four with type 2 diabetes) by Shenoy et al [7] in 2012. These studies demonstrated improved glycemic control during pregnancy and satisfactory maternal and fetal outcomes. The largest prospective randomized trial evaluating the efficacy and safety of insulin detemir in pregnancy vs NPH, both with prandial insulin aspart, was performed in 310 women with T1DM, as already mentioned. Detemir was demonstrated to be as safe and effective as NPH insulin. [8, 9] A subsequent observational study and a recent randomized trial investigating insulin detemir versus NPH in pregnant women with T2DM confirmed the aforementioned results. [21, 22] This was further corroborated by the EVOLVE study, where insulin detemir was compared to other basal insulins (mainly glargine and NPH). [17]

Information about insulin detemir in GDM is scarce and originates mainly from studies with both pregestational and gestational diabetes. [15, 16, 18, 24, 26] Herrera et al. and Ji et al. in their randomized controlled trials comparing insulin detemir versus NPH included both women with GDM and pregestational T2DM who also received short-acting insulin before meals as needed. To our knowledge, our study is the first to investigate exclusively insulin NPH versus detemir in a peer cohort of women with real GDM diagnosed from 24th to 28th week of gestation. In our cohort all women received a single bedtime injection of NPH or detemir per day, in order to correct fasting BG without any additional prandial insulin. Postprandial BG was controlled with proper diabetes pregnancy diet.

Traditionally, improvements in glycemic control during insulin therapy are associated with weight gain. [27] In non-pregnant adults, clinical studies have shown that insulin detemir, compared to NPH, results in less weight gain, especially in the morbidly obese subgroup. [14, 28, 29] Possible pathophysiologic mechanisms include a reduced rate of hypoglycemic events, suppression of hepatic glucose output and elevated satiety signaling within the central nervous system. [30, 31] Weight gain is crucial in the pathophysiology of diabetes, particularly during pregnancy, and is associated with higher risks of adverse pregnancy outcomes, including arterial hypertension and pre-eclampsia, caesarean section, stillbirth, perinatal mortality, macrosomia, premature birth, obesity in childhood and T2DM occurrence in the offspring. [32, 33] Under these circumstances the use of insulin detemir may be beneficial.

In our study, there were no statistical differences concerning maternal weight gain (both per week and throughout pregnancy) between the two groups. These results are in agreement with most other observational cohorts or randomized controlled trials comparing the use of detemir versus NPH in pregnancies with T1DM, T2DM or GDM. [8, 15, 16] Only one recent randomized controlled study comparing detemir versus NPH in 108 pregnant women with T2DM by Bartal et al found that insulin detemir was associated with less weight gain compared with NPH. [22]

In our cohort, no hypoglycemias were recorded in either group and this is probably due to the fact that there was no need for intensification of insulin treatment. Insulin detemir or NPH were injected once daily, while there was no need for rapid-acting insulin. In two observational studies investigating insulin NPH versus detemir in pregnancies with T2DM or GDM the rate of hypoglycemias between the two groups (Detemir vs NPH) was comparable. [21, 24] However, in the randomized controlled trial by Herrera et al in 87 pregnant women with GDM and T2DM, NPH was associated with a higher risk of hypoglycemia compared to insulin detemir. In line with this there are other studies investigating detemir versus NPH in pregnancies with pregestational and gestational diabetes, possibly due to the intensive insulin regimen including short-acting insulins. [15, 16, 22]

Furthermore, no hypertensive disorders were recorded in either group. Previous studies comparing insulin detemir versus NPH in pregnancies with T1DM, T2DM or GDM have shown comparable rates of hypertension. [9, 16, 21, 24] Only the already mentioned randomized study in pregnant women with T2DM by Bartal et al found lower adverse maternal outcomes including hypertensive disorders in the detemir group compared to NPH. [22]

No allergic reactions were recorded in our study in both treatment arms. According to most previous studies adverse drug reactions were rare and similar between the NPH and detemir groups. [16, 21, 22, 24] Notably, in the study by Mathiesen et al only eight women of the 152 of the Detemir group reported adverse events relating to injection sites with one of them withdrawing from the study. [8] In addition, in the study by Herrera et al a higher rate of allergic reactions in women treated with insulin detemir was found, forcing them to switch to an alternate medication. [15]

We found no differences between the two groups with respect to mean fasting and postprandial BG levels in the beginning of insulin treatment and at the end of gestation. These findings are similar to previous observational and randomized controlled studies comparing detemir and NPH in pregnancy. [15, 26] In the randomized trial by Herrera et al no difference was found between the NPH and detemir group concerning mean fasting and postprandial glucose levels, in the percentage of patients who achieved overall glucose control or in time to achieve glucose control. [15]

In our study the detemir group presented a slightly lower HbA1c level at the end of gestation but we consider it of limited clinical significance. Mean BG levels during pregnancy are more sensitive to changes in glucose control over the short time period that these patients are treated for. In addition, the randomized trial of Ji et al comparing NPH versus Detemir in 240 pregnant women with pregestational and gestational diabetes showed that in the early period of treatment, detemir had a better performance than NPH in terms of controlling blood glucose, as fasting and postprandial BG levels after one week of treatment were lower in the detemir group, and the time to reach target was shorter. Further, insulin detemir was at least as effective as NPH in a long-termtreatment as after 3 months HbA1c between the two groups was similar. [16]

In agreement with the study by Mathiesen et al. we found no differences between the two groups in relation to the duration of insulin treatment or the daily insulin dose. [8] Only in the study by Ji et al the total insulin dose in the detemir group was higher than in the NPH group. [16] Nonetheless, in our study insulin doses between the two groups were comparable after adjustment for weight.

Overall, there were no statistically significant differences in neonatal outcomes including birth weight, birth weight adjusted for gestational age, percentage of macrosomia or SGA and rates of preterm delivery or cesarean section. There were no congenital malformations or severe neonatal hypoglycemias, which suggested that insulin detemir was as good as NPH in terms of safety. Our results are consistent with the findings reported by most previous studies. [9, 15, 16, 17, 21, 24] Only the recent randomized study by Bartal et al reported lower rates of adverse neonatal outcomes but with a higher rate of LGA in the detemir group. [21]

To the best of our knowledge this is the largest retrospective study investigating exclusively insulin detemir versus NPH, either of these administered in a single dose at night, in pregnancies with GDM only. In addition, the study has the strength that it has been performed under real life routine conditions in unselected patients in a single center by the same medical team, where the glycemic goals for treatment have been constant during the study period. The majority of the patients were of Caucasian origin and insulin therapy was initiated taking into consideration the increase of the fetal abdomen circumference on ultrasound.

Although a limitation might be the retrospective nature of the design, the study provides real life data complementary to information derived from randomized controlled trials. Most of the women were of the same ethnicity with mean pre-pregnancy BMI under 30 kg/m². Outcomes from this study should be applied carefully in cases of more serious GDM, where intensive insulin regimen is needed and especially in pregnancies with T2DM.

In conclusion, this study provided evidence that insulin detemir and NPH are equally effective and safe with respect to glycemic control and total insulin dose needed, maternal outcomes and complications (hypoglycemia, allergic reactions, weight gain and hypertension), as well as neonatal outcomes (time and mode of delivery, birth weight and rates of macrosomia and SGA). The only significant difference, though minor, was observed in relation to final HbA1c. The lower HbA1c in the detemir group seems not to have clinical significance, as evidenced by the absence of differences with regard to maternal adverse outcomes or neonatal complications, between the two GDM groups. Finally, the only differentiating factor appears to be the cost of the two options, where NPH is the more economical one.

Declarations

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

PK collected the data and wrote the manuscript. SAP and EA edited the manuscript. All authors discussed the findings and reviewed the manuscript. All authors contributed to the article and approved the submitted version.

Ethics Approval

The study has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki). Ethics committee approval was obtained.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

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