PURPOSE:  

• There has been an ongoing debate whether glyburide can be used in place of insulin as a first-line treatment for gestational diabetes mellitus (GDM)  
• Benefits of glyburide and reason for clinical adoption  
  • Insulin carries a significant expense 
  • Major issue of convenience and patient choice, as glyburide is taken orally vs insulin, which is administered by injection  
• Previous studies indicate that glycemic control is similar between glyburide and insulin  
• Question driving this current RCT 
  • More recent studies suggest increased newborn risk with glyburide related to macrosomia and hypoglycemia  
• Sénat et al., (JAMA, 2018) compared glyburide to insulin related to perinatal complications

METHODS: 

• Multicenter randomized noninferiority trial 
  • Non-inferiority design as per ACOG recommendations  
  • Due to recognized benefits of glyburide, acceptable to demonstrate that the oral approach is at least not clinically worse as opposed to more typical ‘superiority’ studies that determine if one option is better than the other 
• 13 centers in France  
• Participants 
  • Singleton pregnancy with GDM diagnosis between 24 and 34 weeks of gestation  
  • Diagnosis using a 75-g oral glucose tolerance test resulted in 1 or more abnormal blood glucose values 
    • Fasting: > 92 mg/dL (5.1 mmol/L) 
    • 1-hour postprandial: >180 mg/dL (10 mmol/L) 
    • 2-hour postprandial: >153 mg/dL (8.5 mmol/L)  
• Exclusion criteria
  • Diabetes: Fasting blood glucose concentration greater than 126 mg/dL (7 mmol/L) 
  • Glucose screening test performed before 24 weeks of gestation 
  • Multiple pregnancy | Chronic hypertension | Preeclampsia |Known liver or renal disease 
• GDM Management 
  • Nutrition education 25 kcal/kg (overweight/obese)and 35 kcal/kg per day (normal weight)  
  • Glucose self-monitoring 4 times daily (fasting and 2 hours after each meal) 
• Women randomized if glycemic targets not achieved 
  • After 10 days of diet, ≥2 blood glucose values above the targets were observed over a week  
• Targets 
  • Fasting: ≥95 mg/dL 
  • 2-hour postprandial: ≥120 mg/dL 
• Gyburide arm 
  • 2.5 mg orally once per day  
  • Increase 4 days later by 2.5 mg and then by 5 mg every 4 days in 2 doses, morning and evening, up to a maximum of 20 mg/d 
• Insulin arm  
  • Start rapid analogs at 4 IU given subcutaneously before meals, 1 to 3 times per day as necessary  
  • Increase by 2 IU every 2 days based on postprandial blood glucose value. 
  • If required, the starting dosage for basal or intermediate insulin was 4 IU to 8 IU given subcutaneously at bedtime and increased by 2 IU every 2 days according to the morning fasting blood glucose value 
  • Women were taught to self-adjust  
• Primary Outcome: Composite GDM perinatal complications  
  • Macrosomia | Neonatal hypoglycemia | Hyperbilirubinemia 
• Secondary Outcomes 
  • Neonatal mortality and morbidities including NICU admission, ponderal index, pH  
  • Maternal outcomes including glycemic control, preterm delivery, perineal trauma, % switch to insulin  
• Statistical Analysis/Design (Primary Outcome) 
  • Insulin estimated to result in 18% composite perinatal complications 
  • Providers would accept a 25% rate of perinatal complications with glyburide  
  • The noninferiority margin was set at 7% based on a 1-sided 97.5% confidence interval 
  • Non-inferior if upper margin doesn’t surpass 7% difference

RESULTS:

• 367 women were randomized to glyburide and 442 to the insulin group  
• Mean glyburide dose 5.4 mg  
• Overall, no major differences in patient demographics or blood glucose values at inclusion  
• Primary Outcome (composite perinatal complications) not significant
  • 27.6% in glyburide group vs 23.4% in insulin group 
  • Difference, 4.2%; 1-sided 97.5% CI, −∞ to 10.5%; P = .19 
  • Upper limit exceeds the 7% threshold
  • When adjusted for multiparity and gestational age, upper limit still above threshold  
• Secondary Outcomes  
  • Neonatal outcomes: No significant differences  
  • Maternal glucose better controlled in glyburide group vs insulin (significant for fasting levels)  
  • 18% of women on glyburide switched to insulin  
  • Patient satisfaction higher with glyburide  
    • 23.6% vs 5% (P <.001)  
  • Maternal severe hypoglycemic episodes higher with glyburide  
    • 3.8% vs 1% (difference, 2.8%; 95% CI, 0.2%-5.5%; P = .02) 

CONCLUSION: 

• Higher rate of primary outcome composite complications in glyburide group is due to neonatal hypoglycemia and consistent with previous reports  
• This study did not find significant in-group differences in macrosomia, hyperbilirubinemia, admission to NICU or RDS  
• Authors state that “These findings do not justify the use of glyburide as a first-line treatment.”
• Accompanying editorial notes  
  • Minimal literature on long term effects of glyburide on offspring (fetal concentrations are 50 to 70% of maternal levels)   
  • There may be issues in this present study related to underdosing of glyburide and further research is warranted
  • The authors’ “conclusion is reasonable based on current evidence”

Learn More – Primary Sources:

Effect of Glyburide vs Subcutaneous Insulin on Perinatal Complications Among Women With Gestational Diabetes – A Randomized Clinical Trial

JAMA Editorial: Insulin vs Glyburide for Gestational Diabetes 

Related ObG Topics:

ACOG and SMFM Both Release Guidance on Gestational Diabetes – Insulin vs Metformin for First-Line Therapy?

Screening for Gestational Diabetes: The ‘2 Step’ Approach

What Is The ‘One-Step’ GDM Screening Approach?

Updated ACOG Guidance on Gestational Diabetes