Detemir vs neutral protamine Hagedorn insulin for diabetes mellitus in pregnancy: a comparative effectiveness, randomized controlled trial





Background


Insulin detemir, being used increasingly during pregnancy, may have pharmacologic benefits compared with neutral protamine Hagedorn.


Objective


We evaluated the probability that compared with treatment with neutral protamine Hagedorn, treatment with insulin detemir reduces the risk for adverse neonatal outcome among individuals with type 2 or overt type 2 diabetes mellitus (gestational diabetes mellitus diagnosed at <20 weeks’ gestation).


Study Design


We performed a multiclinic randomized controlled trial (September 2018 to January 2020), which included women with singleton gestation with type 2 or overt type 2 diabetes mellitus who sought obstetrical care at ≤21 weeks’ gestation. Participants were randomized to receive either insulin detemir or neutral protamine Hagedorn by a clinic-stratified scheme. The primary outcome was a composite of adverse neonatal outcomes, including shoulder dystocia, large for gestational age, neonatal intensive care unit admission, respiratory distress (defined as the need of at least 4 hours of respiratory support with supplemental oxygen, continuous positive airway pressure or ventilation at the first 24 hours of life), or hypoglycemia. The secondary neonatal outcomes included gestational age at delivery, small for gestational age, 5-minute Apgar score of <7, lowest glucose level, need for intravenous glucose, respiratory distress syndrome, need for mechanical ventilation or continuous positive airway pressure, neonatal jaundice requiring therapy, brachial plexus injury, and hospital length of stay. The secondary maternal outcomes included hypoglycemic events, hospital admission for glucose control, hypertensive disorder of pregnancy, maternal weight gain, cesarean delivery, and postpartum complications. We used the Bayesian statistics to estimate a sample size of 108 to have >75% probability of any reduction in the primary outcome, assuming 80% power and a hypothesized effect of 33% reduction with insulin detemir. All analyses were intent to treat under a Bayesian framework with neutral priors (a priori assumed a 50:50 likelihood of either intervention being better; National Clinical Trial identifier 03620890).


Results


There were 108 women randomized in this trial (57 in insulin detemir and 51 in neutral protamine Hagedorn), and 103 women were available for analysis of the primary outcome (n=5 for pregnancy loss before 24 weeks’ gestation). Bayesian analysis indicated an 87% posterior probability of reduced primary outcome with insulin detemir compared with neutral protamine Hagedorn (posterior adjusted relative risk, 0.88; 95% credible interval, 0.61–1.12). Bayesian analyses for secondary outcomes showed consistent findings of lower adverse maternal outcomes with the use of insulin detemir vs neutral protamine Hagedorn: for example, maternal hypoglycemic events (97% probability of benefit; posterior adjusted relative risk, 0.59; 95% credible interval, 0.29–1.08) and hypertensive disorders (88% probability of benefit; posterior adjusted relative risk, 0.81; 95% credible interval, 0.54–1.16).


Conclusion


In our comparative effectiveness trial involving individuals with type 2 or overt type 2 diabetes mellitus, use of insulin detemir resulted in lower rates of adverse neonatal and maternal outcomes compared with neutral protamine Hagedorn.


Introduction


Approximately 14.8 million people of reproductive age in the United States have diabetes mellitus, and at least 2.2% of current US births occur to women with pregestational diabetes mellitus. Individuals with type 2 diabetes mellitus are at increased risk of adverse neonatal and pregnancy outcomes, including pregnancy loss, congenital anomalies, hypertensive disorders, cesarean delivery, large-for-gestational-age (LGA) neonates, neonatal intensive care unit (NICU) admissions, and perinatal mortality. Considering the myriad of treatment options, it is essential that appropriate treatment is given to women with type 2 diabetes mellitus during pregnancy, as glucose control decreases the frequency of adverse peripartum outcomes.


Insulin is the preferred agent for the management of diabetes mellitus in pregnancy because it does not cross the placenta and oral agents are purportedly insufficient to overcome the insulin resistance in type 2 diabetes mellitus. Basal insulins, including neutral protamine Hagedron (NPH; isophane insulin) and the insulin analogs—insulin glargine and insulin detemir—suppress uncontrolled hepatic glucose production, are relatively long acting, and are usually injected once or twice daily.



AJOG at a Glance


Why was this study conducted?


This study aimed to determine whether treatment with insulin detemir of pregnant women with type 2 or overt type 2 diabetes mellitus (gestational diabetes mellitus diagnosed at <20 weeks’ gestation) reduces adverse neonatal and maternal outcomes compared with treatment with neutral protamine Hagedorn (NPH).


Key findings


In this comparative effectiveness randomized controlled trial of pregnant women with type 2 or overt type diabetes mellitus, the use of insulin detemir resulted in lower rates of adverse neonatal and maternal outcomes compared with the use of NPH.


What does this add to what is known?


Our study provided a randomized trial based on data from the United States focusing on women with type 2 diabetes mellitus and evaluating neonatal outcomes between detemir and NPH.



The main difference between NPH and insulin analog (eg, detemir) is the pharmacodynamics. NPH peaks at 4 to 12 hours after injection with a duration of action around 14 hours, whereas insulin detemir is characterized by a gentle rise and fall with a longer duration of action (18 to 20 hours) in most patients. Because insulin analogs show more favorable properties of action and a theoretical advantage, it is thought that treatment with these newer insulin analogs might lead to a beneficial effect, for example, less hypoglycemia, weight gain, or a better metabolic control, possibly resulting in less diabetic complications. Outside of pregnancy, clinical trials comparing efficacy outcomes with basal insulin analogs report that insulin analogs are mostly noninferior or better than other insulins, vis-à-vis reducing the incidence of hypoglycemia and weight gain. Although there are studies in pregnancy comparing insulin detemir and NPH, there is no randomized trial on the neonatal benefits of insulin analog in people with type 2 diabetes mellitus. Therefore, at present, there are insufficient data to determine what type of insulin reduces neonatal adverse outcomes with type 2 diabetes mellitus with minimum adverse events, such as maternal hypoglycemia. ,


We conducted a multiclinic randomized controlled trial (RCT) among people with type 2 or overt type 2 diabetes mellitus (gestational diabetes mellitus diagnosed at <20 weeks’ gestation) treated with insulin detemir vs NPH. We hypothesized that treatment with insulin detemir will reduce adverse neonatal outcomes and reduce the number of maternal hypoglycemic events during pregnancy compared with treatment with NPH.


Materials and Methods


Trial design


We conducted a multiclinic open-label, comparative effectiveness, RCT at 6 clinic sites. Our protocol was approved by the institutional review board at the McGovern Medical School (HSC-MS-18-0575) and registered in ClinicalTrials.gov before starting enrollment (NCT 03620890). All participants provided written informed consent to participate in the research study.


Participants


Women with a singleton gestation and type 2 or overt type 2 diabetes mellitus who sought obstetrical care at ≤21 weeks’ gestation were screened for eligibility. Overt type 2 diabetes mellitus was defined according to the American Diabetes Association criteria, including people with overt diabetes mellitus diagnosed before 20 weeks’ gestation using either hemoglobin A1c (HbA1c) of ≥6.5 or fasting glucose of ≥126 mg/dL or random blood glucose of ≥200 mg/dL or 2-step method (50 g glucose challenge test of >135 mg/dL followed by 100 g glucose challenge test with at least 2 values above thresholds: fasting blood glucose of >90 mg/dL, 1-hour postprandial value of >180 mg/dL, 2-hour postprandial value of >155 mg/dL, and 3-hour postprandial value of >140 mg/dL). ,


Those with type 1 diabetes mellitus, age younger than 18 years, major fetal anomaly, allergy or previous adverse reaction to NPH or insulin detemir, diabetes nephropathy (Cr≥1.5), or diabetic proliferative retinopathy were excluded. We defined the inclusion and exclusion criteria during our study design phase, before the study started, and made no changes after enrollment started.


Randomization and masking


Participants were randomly allocated in 1:1 ratio to receive either insulin detemir or NPH prescriptions by the treating clinicians. A computer-generated randomization sequence was prepared, with permuted blocks, and was stratified according to study site by the study statistician. The medication based on the computer-generated list was typed out on a piece of paper with the insulin regimen. The piece of paper was placed in an opaque envelope and numbered according to the computer-generated list. Envelopes were kept secured at the clinic sites and were managed by the research team. Owing to the nature of the intervention, treating clinicians and the participants could not be blinded for their assigned allocation.


Trial interventions


Following allocation, the participants were instructed to start treatment on the same day. Individual’s weight was obtained at the visit and the initial daily total insulin dose of detemir or NPH, and the short-acting insulin was determined on the basis of the weight and treatment according to the recommended guidelines. In the first trimester of pregnancy, the patient weight in kilograms was multiplied by 0.7, in the second trimester of pregnancy by 0.8, and in the third trimester of pregnancy by 0.9 for the total daily units of insulin. , In the insulin detemir group, the total daily dose of insulin was divided into 50% insulin detemir and 50% short-acting insulin. Based on clinician’s preference, insulin detemir dose could be divided in half and then injected in the morning and evening, 12 hours apart. Short-acting insulin was divided with one-third each being injected with breakfast, lunch, and dinner meals. In the NPH insulin group, approximately 60% of the total daily dose was given in the morning and 40% in the evening. For the total morning dose, two-thirds was NPH and one-third was the short-acting insulin. The total evening dose was halved: the short-acting insulin injected at dinner, whereas the NPH was injected at bedtime.


Other than the type of long-acting insulin, participants were managed according to usual obstetrical care. , Participants were instructed to check glucose levels at fasting and 1 or 2 hours after meal. The treating clinicians adjusted the insulin dose to maintain good glucose control based on accepted targets: fasting glucose of <95 mg/dL, 2-hour postprandial values of <120 mg/dL, overall mean glucose of <100 mg/dL. According to our usual practice, each individual had at least 1 meeting with a registered dietitian and diabetes care and education specialist to learn how to self-administer insulin and were followed up in a Maternal-Fetal Medicine clinic. Participants were followed up every 1 to 2 weeks, or as necessary, determined by their glucose control, until delivery.


Use and type of short-acting insulin, insulin adjustment, and the timing of delivery were at the discretion of each participant’s maternal-fetal-medicine subspecialist.


Trial outcomes


The primary outcome was a composite of adverse neonatal complications and consisted of 1 or more of the following: shoulder dystocia (defined as the need for any extra maneuvers, other than gentle downward traction of the fetal head to deliver the fetal body after the fetal head has been delivered), LGA (defined as birthweight over the 90th percentile of the expected value according to gestational age [GA]), NICU admission, neonatal hypoglycemia (blood sugar of <40 mg/dL in the first 24 hours of life or <50 mg/dL after or need for medical therapy), respiratory distress (need for at least 4 hours of respiratory support with supplemental oxygen, continuous positive airway pressure (CPAP) or ventilation at the first 24 hours of life). Neonatal secondary outcomes included GA at delivery, small for GA (defined as birthweight below the 10th percentile for GA), 5-minute Apgar score of <7, lowest glucose level, need for intravenous glucose, respiratory distress syndrome (RDS; defined as the presence of clinical signs of respiratory distress with oxygen requirement and a classical chest x-ray finding), need for mechanical ventilation or CPAP, neonatal jaundice requiring therapy, brachial plexus injury, and hospital length of stay.


Secondary maternal outcomes included hypoglycemic events (defined as <60 mg/dL), antepartum hospital admission for glucose control, hypertensive disorder of pregnancy, maternal weight gain (from randomization to delivery), cesarean delivery, and postpartum complications, such as wound infection and endometritis.


The maternal demographic, antepartum, labor course, and outcomes were extracted from the electronic medical record and collected using Research Electronic Data Capture (REDCap) software. Furthermore, the neonatal outcomes until discharge were culled and entered in REDCap.


Sample size


The sample size was calculated on the basis of previous data on composite adverse neonatal outcomes of 43% in women with type 2 diabetes mellitus. We used the Bayesian statistics to estimate a sample size using a probability of 75% or greater for superiority. Given the evidence of noninferiority or superiority of detemir compared with NPH, the fact that both treatments are commonly used, there is no evidence of important differences in side effects, and there is no difference in insurance coverage during pregnancy, we decided that a threshold of >75% posterior probability of reducing neonatal adverse outcomes by any amount would justify the use of detemir in this population. A sample size of 108 provided 80% power to identify the most effective treatment, assuming the NPH group had a true adverse outcome rate of 43% and the true adverse rate was 29% in the detemir group (33% reduction). Of note, we designed this study as a Bayesian RCT to be able to provide probabilities of benefit or harm from either intervention. It is not possible to calculate these quantities from frequentist statistics. Furthermore, P values and confidence intervals (CIs) are often misinterpreted and incorrectly dichotomized into “significant” and “nonsignificant” results. To avoid these pitfalls, we chose a Bayesian design and analysis that is less prone to these issues while providing probabilities that can be directly used for decision-making.


Data analysis


Intention-to-treat analyses were conducted under a Bayesian framework. The probability and magnitude of treatment benefit of insulin detemir compared with NPH were assessed for each outcome. There were 3 different types of outcomes: binary (eg, composite primary outcome), discrete (total days in hospital), and continuous (eg, weight gain). Binary outcomes were evaluated with a logistic model. A negative binomial model was used to assess discrete outcomes. For both cases, we conservatively set a neutral prior probability centered at a relative risk (RR) of 1.0 (ie, a priori no effect on the outcome) and a 95% credible interval (CrI) of 0.25 – 4.0. Continuous outcomes were analyzed with a linear regression model using the default prior distribution provided by the brms package. All models included the stratifying variable clinic site as a covariate. We report the estimated posterior median RR or mean group difference with a 95% CrI for each outcome. A 95% CrI is interpreted as there being a 95% probability of the true RR being in this interval. The probability of treatment benefit was determined by the posterior probability that an RR (for binary and discrete outcomes) or a mean group difference (for continuous outcomes) is less than 1 or 0, respectively. To validate that there is no effect of fetal loss (ie, first-trimester miscarriage, termination of pregnancy); we conducted a posthoc sensitivity analysis. Under the same Bayesian framework, the probability of treatment benefit and its CrI were obtained on basis of the outcome as a composite of adverse neonatal outcomes and/or fetal death.


All analyses were conducted in R software (version 3.6.2) using the brms package.


Results


Between September 2018 and January 2020, 173 individuals with diabetes mellitus presented for prenatal care before 21 weeks’ gestation, and among them, 57 (32.9%) met 1 of the exclusion criteria, and 8 (4.6%) declined participation. Of the 108 people randomized, 57 were allocated to insulin detemir, and 51 were allocated to NPH. No patient was lost to follow-up. However, the primary and secondary outcomes were not available in a total of 5 of 108 participants (4.6%). The reasons were that 2 participants in the insulin detemir group and 1 participant in the NPH group had first-trimester miscarriage, 1 participant in the insulin detemir group had major fetal anomaly (holoprosencephaly) diagnosed after randomization and underwent termination of pregnancy, and 1 participant in the insulin detemir group had major fetal anomalies (hypoplastic left heart and sacral agenesis) diagnosed after randomization with a stillbirth at 22 weeks’ gestation ( Figure 1 ). All participants followed their assigned treatment.




Figure 1


Flow diagram

CONSORT flow diagram.

CONSORT , Consolidated Standards of Reporting Trials.

Fishel Bartal et al. Long-acting insulin for type 2 diabetes. Am J Obstet Gynecol 2021.


Of the 108 participants enrolled, 67 (62%) were Hispanic, and 28 (26%) were African American. Furthermore, among the participants, 89 (82%) had a body mass index greater than 30 kg/m 2 ; 86 (80%) had type 2 diabetes mellitus diagnosed before pregnancy, with a median HbA1c of 7.6 (interquartile range [IQR], 6.2–10.0); 22 (20%) had overt type 2 diabetes mellitus diagnosed before 20 weeks’ gestation, with a median HbA1c of 6.7 (IQR, 5.8–7.6). The baseline maternal characteristics were similar between the groups. In both groups, about 2 of 10 participants were recruited from private practice. Moreover, 38 participants (71.7%) in the insulin detemir group also received rapid-acting insulin (ie, lispro, aspart), and 41 participants (82%) in the NPH group received either regular insulin (n=31) or rapid-acting insulin (n=10) ( Table 1 ). Of 108 participants, 95 (88%) required twice-a-day dosing of the basal analogs (84% for insulin detemir vs 92% for NPH). For the insulin detemir group, the median daily starting dose was 31 units (IQR, 20–40), with a median maximal dose of 60 units (IQR, 40–98). For the NPH group, the median daily starting dose was 40 units (IQR, 25–48), and the maximal dose was 54 units (IQR, 41–80). The primary outcome occurred in 31 of 53 participants (58%) in the insulin detemir group and 35 of 50 participants (70%) in the NPH group. Bayesian analysis using a neutral prior indicated an 87% posterior probability of reduced primary outcome with insulin detemir compared with NPH, with a posterior adjusted RR (aRR) of 0.88 (95% CrI, 0.61–1.12) ( Figure 2 ). The most common morbidities in the neonatal composite outcomes were NICU admission, respiratory distress, and neonatal hypoglycemia. From 29 neonates admitted to the NICU in the insulin detemir group, 16 (55.2%) were admitted for respiratory support, and 13 (44.8%) were admitted for glycemic control. From 31 neonates admitted to the NICU in the NPH group, 22 (71%) were admitted for respiratory support, 7 (22.5%) for glycemic control, and 2 (6.5%) for low birthweight. The main difference between insulin detemir and NPH in the rate of the primary outcome was driven by the difference in the respiratory distress rate; 93% probability was identified for the reduction in respiratory distress with detemir ( Table 2 ).



Table 1

Baseline characteristics












































































































Characteristic Detemir (n=57) NPH (n=51)
Age (y) 32.1±6.2 32.5±6.0
Age≥35 20 (35.1) 19 (37.3)
Race or ethnic group
Non-Hispanic White 3 (5.2) 6 (11.7)
Non-Hispanic Black 14 (24.6) 14 (27.5)
Hispanic 36 (63.2) 31 (60.8)
Asian 4 (7.0) 0 (0)
Had private insurance for prenatal care 22 (38.6) 18 (35.3)
Nulliparous 5 (8.8) 7 (13.7)
Prepregnancy body mass index (kg/m 2 ) 36.2 (32.5–40.8) 34.2 (29.9–37.2)
BMI≥30 51 (89.5) 38 (74.5)
Diabetes mellitus diagnosed before pregnancy 44 (77.2) 42 (82.4)
HbA1c gestational age 12.1 (8.9–14.4) 12.4 (8.4–16.0)
First A1c levels 7.1 (6.1–9.0) 8.0 (6.3–10.5)
A1c≥6.5% 37 (64.9) 34 (66.6)
Chronic hypertension 12 (21.1) 17 (33.3)
Depression or anxiety 7 (12.3) 9 (17.6)
Thyroid disease 2 (3.5) 4 (7.8)
Gestational age at first clinic visit 12.1 (9.4–13.6) 12.0 (8.8–15.4)
Smoking during pregnancy 2 (3.5) 0 (0)
Alcohol use during pregnancy 2 (3.5) 0 (0)
Substance use during pregnancy 3 (5.3) 1 (2.0)
Gestational age at randomization 13.0 (10.3–15.4) 12.7 (9.1–16.4)
Use of rapid- or short-acting insulin 38 (71.7) 41 (82.0)
Aspirin use during pregnancy 27 (50.9) 29 (58.0)

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Jul 5, 2021 | Posted by in GYNECOLOGY | Comments Off on Detemir vs neutral protamine Hagedorn insulin for diabetes mellitus in pregnancy: a comparative effectiveness, randomized controlled trial

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