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Grand Rounds
CMECNE

The Great GDM Debate: Glyburide vs Insulin RCT Results and Associated Perinatal Complications

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Learning Objectives and CME/Disclosure Information

This activity is intended for healthcare providers delivering care to women and their families.

After completing this activity, the participant should be better able to:

1. Describe why the authors of this study felt that another RCT on glyburide vs insulin for the treatment of GDM would be of value
2. Discuss the results and conclusions of this non-inferiority study comparing glyburide to insulin

Estimated time to complete activity: 0.5 hours

Faculty:

Susan J. Gross, MD, FRCSC, FACOG, FACMG
President and CEO, The ObG Project

Disclosure of Conflicts of Interest

Postgraduate Institute for Medicine (PIM) requires faculty, planners, and others in control of educational content to disclose all their financial relationships with ineligible companies. All identified conflicts of interest (COI) are thoroughly vetted and mitigated according to PIM policy. PIM is committed to providing its learners with high quality accredited continuing education activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of an ineligible company.

The PIM planners and others have nothing to disclose. The OBG Project planners and others have nothing to disclose.

Faculty: Susan J. Gross, MD, receives consulting fees from Cradle Genomics, and has financial interest in The ObG Project, Inc.

Planners and Managers: The PIM planners and managers, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CHCP, Judi Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz, MSN, RN, CHCP have nothing to disclose.

Method of Participation and Request for Credit

Fees for participating and receiving CME credit for this activity are as posted on The ObG Project website. During the period from May 9 2018 through 07/15/2022, participants must read the learning objectives and faculty disclosures and study the educational activity.

If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation. Upon registering and successfully completing the post-test with a score of 100% and the activity evaluation, your certificate will be made available immediately.

For Pharmacists: Upon successfully completing the post-test with a score of 100% and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service within 4 weeks.

Joint Accreditation Statement

In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and The ObG Project. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Physician Continuing Medical Education

Postgraduate Institute for Medicine designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Continuing Nursing Education

The maximum number of hours awarded for this Continuing Nursing Education activity is 0.4 contact hours.

Designated for 0.4 contact hours of pharmacotherapy credit for Advance Practice Registered Nurses.

Read Disclaimer & Fine Print

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 

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What Is The ‘One-Step’ GDM Screening Approach?
Updated ACOG Guidance on Gestational Diabetes

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Disclosure of Unlabeled Use

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

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Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information
presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

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