EAL

GDM: Pharmacologic Therapy (2008)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The purpose of this study was to investigate the association between glyburide dose, degree of severity in gestational diabetes mellitus (GDM), level of glycemic control, and pregnancy outcome in insulin- and glyburide-treated patients.

Inclusion Criteria:

Singleton pregnancies
Women with gestational diabetes with fasting plasma glucose concentrations of at least 95 mg/dl and less than 140 mg/dl on oral glucose-tolerance testing.
Women fasting plasma glucose concentrations of < 95 mg/dl were included if they were unable to keep their fasting glucose concentrations < 95 mg/dl and/or post-prandial blood glucose levelsl <120 mg/dl on dietary management.

Exclusion Criteria:

Excluded if not included above.

Description of Study Protocol:

Recruitment: Women were recruited from maternal health clinics in San Antonio Texas.

Design: Randomized Controlled Trial, secondary analysis.

All subjects were instructed in standard nutritional recommendations for GDM. Diet prescriptions were designed to provide 25 kcal/kg body weight for obese women and 35 kcal/kg body weight for the nonobese.

Women were assigned to either receive glyburide or insulin and monitored through out their pregnancy. Neonates were assessed at birth.

The level of GDM severity, categorized by 10 mg/dl increments was defined using the fasting plasma glucose value on the OGTT. Women with BMI 27.3 or higher were considered obese.

Maternal and neonatal outcome characteristics were stratified for severity of GDM, glyburide dose and level of glycemic control. The efficacy of insulin and glyburide therapies was compared for each GDM severity level.

A composite outcome variable was created for all infants if at least 1 of the following was present: metabolic complications, LGA/macrosomia, neonatal intensive care unit admission for > 24 horus and the need for respiratory support.

Blinding used (if applicable): none

Intervention (if applicable)

The glyburide group received glyburide at 2.5 mg orally initially and increased as indicated the following week by 2.5 mg and thereafter by 5 mg weekly to a total of 20 mg to achieve glycemic control.

Women who were assigned insulin were given 0.7 u per kg actual body weight at admission, given subcutaneously three times daily and increased weekly as necessary.

Patients were treated to attain the same metabolic goals based on self-monitoring blood glucose results. Mean blood glucose < 95 mg/dl were considered well-controlled, and those with mean blood glucose > 95 mg/dl were considered poorly controlled.

Statistical Analysis

Analysis was performed using chi-square and Fisher exact test for categorical data. Odds ratio was calculated by the Mantel-Haenszel test and multivariant analysis (logistic regression) was performed to assess the extent to which various risk factors affect or contribute to neonatal outcome. Pearson's correlation was calculated for continuous data to study the association between treatment modality and explanatory variables.

Data Collection Summary:

Timing of Measurements

Measurements of neonates were done immediately after birth and up to the first 4 hours of life.

Dependent Variables

Maternal glycemic control
Neonatal outcomes

Independent Variables

Glyburide dosage
Insulin dosage

Control Variables

Severity levels of GDM
Mean blood glucose
Weight gain in pregnancy
Previous macrosomia
Obesity
Parity
Race/ethnicity
Maternal age

Description of Actual Data Sample:

Initial N: 404 women (201 glyburide group, 203 insulin group)

Attrition (final N): 404

Age: ranged from 18- 40 years

Ethnicity: 83% were Hispanic (mostly Mexican-American), 12% were non-Hispanic whites and 5% were black

Other relevant demographics: all were Medicaid recipients, majority had completed 10th grade

Anthropometrics

There were no signficant differences between groups in age, pre-pregnancy BMI, results of OGTT or previous delivery of infant with macrosomia, or hemoglobin AIC values before treatment. There were no signficant differences in weight gain during pregnancy between the 2 groups.

Location: San Antonio, Texas

Summary of Results:

**Perinatal outcome by severity of gestational diabetes (fasting plasma glucose from the OGTT**)
Fasting plasma glucose in the oral OGTT	< 95 mg/dl (Low)	< 95 mg/dl (Low)	> 95 mg/dl (High)	> 95 mg/dl (High)	P value
	*Insulin*	*Glyburide*	*Insulin*	*Glyburide*
Gestational age at delivery	38.5 +1.9	38.8 + 1.5	38.2 + 2.1	38.5 + 1.6	NS
Large for Gestational age	7.7 %	8.8%	17.8 %	18.4 %	0.01 between low and high groups
Macrosomia	2.0%	6.3%	8.0%	9.2 %	NS
Composite outcome	25.3 %	27.5 %	30.7 %	29.1 %	NS

**Logistic regression for LGA as dependent variable**
Variable	Odds Ratio	95 % CI
GDM severity	2.13	1.09 - 4.18
Mean blood glucose	1.99	1.04 - 3.83
Weight gain in pregnancy	3.81	1.81 - 8.05
Previous delivery of infant with macrosomia	3.73	1.70- 8.18

Other Findings

A positive association was found between maternal prepregnancy weight and pharmacologic dose for both insulin ( r=0.50, p= 0.0001) and glyburide (r = 0.27, p=0.0002).

With glyburide therapy, there was a signficant difference between the dose in the patients with lower diabetes severity and those with the most severe disease (p = 0.001). A significantly lower dose of insulin was given to those patients in the low severity class (p= 0.004).

Author Conclusion:

In all severity levels of GDM, the success rate for achieving established levels of glycemic control is similar in insulin- and glyburide-treated patients. As the level of disease severity increases, the success rate for achieving established levels of glucose control decreases. For the majority of patients, glyburide therapy can be the drug of choice when diet treatment fails. Treatment modality (glyburide versus insulin) was not a contributing risk for adverse neonatal outcome.

Funding Source:

University/Hospital:

University Hospital of Columbia University

Reviewer Comments:

Further analysis of a previous study, some original details not included.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	N/A

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	N/A
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		???
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	???
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	???
	4.4.	Were reasons for withdrawals similar across groups?	???
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		N/A
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	N/A
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	N/A
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	???
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	N/A
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes