Oral Hypoglycemic Agents vs Insulin in Management Of

Oral hypoglycemic agents vs insulin in management of

gestational diabetes: a systematic review and metaanalysis

BACKGROUNDS

• GDM is associated with increased risks of obstetric morbidity, fetal macrosomia, and perinatal death

• Subcutaneous insulin therapy has been the mainstay of treatment

BACKGROUNDS

• Oral hypoglycemic agents (OHAs) have traditionally been avoided in women with diabetes in pregnancy because of – The potential risks of neonatal hypoglycemia– Teratogenicity associated with placental transfer to

the fetus• There are conflicting studies regarding transfer

of glyburide across placenta• The in vitro studies have shown minimal transfer

BACKGROUNDS

• A recent in vivo study has shown transfer at term but mentions that glyburide appears safe to fetus at maternal doses up to 20 mg/d

• Metformin does cross the placenta but acts as an insulin sensitizer, not insulin secretagogue, and is less likely to cause severe neonatal hypoglycemia

BACKGROUNDS

• From animal and human data, it was found that glyburide and metformin confer a low risk of teratogenicity

• Conventionally, treatment for gestational diabetes has been offered in the form of dietary manipulation with supplementary insulin if adequate glycemic levels are not achieved

BACKGROUNDS

• the use of OHAs may provide the flexibility of treatment and high efficacy for both patients and an increasingly overburdened clinical service

MATERIALS AND METHODS

• Identification of relevant trials– all relevant published and nonpublished

randomized controlled clinical trials comparing oral hypoglycemic agents and insulin

– search on Medline, Embase, and Cochrane without language restriction and using a combination of MeSH and text words for all RCTs comparing oral hypoglycemic agents and insulin

MATERIALS AND METHODS

• Identification of relevant trials (cont.)– For our literature search, we secured the expertise

of librarians from our hospital and also the Royal College of Obstetricians and Gynecologists (RCOG)

– set up a literature search alert for the local National Health Service library for any new articles relevant to our search

– letters, editorials, references in journal articles, and text books were reviewed

MATERIALS AND METHODS

• Methods– followed the guidelines for metaanalysis and

systematic reviews of health care interventions outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement

MATERIALS AND METHODS• Inclusion and exclusion criteria

– 1. Population was patients with gestational diabetes– 2. Study design was RCTs– 3. Interventions we compared were insulin vs oral hypoglycemic

agents (metformin or glyburide)– 4. Outcomes: studies that measured one or more of the following:

maternal glycemic control, neonatal hypoglycemia, birthweight, macrosomia, birth injuries, neonatal intensive care unit (NICU) admissions, small for gestational age (SGA) and preterm births, intrauterine fetal deaths (IUFD), congenital anomalies, maternal hypoglycemia or ketoacidosis, hypertensive complications, incidence of cesarean section, side effects of treatment, and maternal satisfaction/quality of life

MATERIALS AND METHODS

• Quality assessment and data extraction– All abstracts were evaluated independently by 2

reviewers and disagreements were resolved by discussion– Final eligibility of studies was decided by consensus– full articles of studies that met the inclusion criteria were

examined independently by 2 authors and data extracted independently for methodological qualities and outcome measures as per preagreed proformas

– Final data and manuscript were reviewed by all 4 authors.

MATERIALS AND METHODS

• Statistical analysis– All metaanalyses were performed using StatsDirect

statistical software (version 2.5.7; Stats Direct Ltd, Cheshire, UK)

– For all dichotomous outcomes, we calculated the pooled odds ratio and 95% confidence interval using the random-effects model (DerSimonian Liard)

– Heterogeneity or noncombinability between trials was assessed by using Cochran Q test for continuous variables and Woolf Q test for dichotomous variables

MATERIALS AND METHODS

• Statistical analysis (cont.)– Homogeneity across studies was assessed by

qualitative visual interpretation of Forest and L’Abbes plots

RESULTS

RESULTS

RESULTS

RESULTS

RESULTS

RESULTS

RESULTS

RESULTS

RESULTS

RESULTS

RESULTS• Other neonatal outcomes : there was no significant

difference between the 2 treatment groups in– Incidence of admission to NICU(OR, 0.84; 95% CI, 0.61–1.17)– neonatal respiratory distress (OR, 0.83; 95% CI, 0.45–1.53)– incidence of birth injuries (OR, 1.01; 95% CI, 0.51–1.99)– incidence of SGA (6.75% OHA vs 9.85% insulin; OR, 0.51; 95%

CI, 0.12–2.12)– incidence of preterm births (11.9% OHA vs 7.6% insulin; OR,

1.63; 95% CI, 1.01–2.63)– Congenital anomalies (OR, 0.81; 95% CI, 0.51–1.99; P =0.5)– incidence of IUFD (OR, 1.0; 95% CI, 0.17–5.83)

RESULTS

• Other neonatal outcomes (cont.)– Patients with gestational diabetes receive oral

hypoglycemic agents well after organogenesis– the rates of congenital anomalies were similar in both

groups– there were 2 cases of IUFD in each group : Rowan et al

reported 1 IUFD in the insulin group who had Budd Chiari syndrome , Moore et al reported another in the metformin group because of birth asphyxia probably from cord accident , Langer et al reported 1 IUFD in each group, probably with congenital anomalies as causative

RESULTS

• Maternal complications– The maternal hypoglycemia rate was reported in 2

studies and was 8.8% in OHA group and 22.2 % in the insulin group (OR, 0.34, 95% CI, 0.02–5.82)

– Incidence of maternal hypertensive disorders was reported in 2 studies and was slightly higher in the insulin group (10.65% vs 8.16%; OR, 0.75; 95% CI, 0.50 –1.12)

– the differences were not statistically significant

RESULTS

RESULTS

• Patient preference and quality of life– Was reported in 1 study only– Satisfaction was significantly higher in the OHA

(metformin) group (76.6% vs 27.2%; P .001)– Acceptability was reported higher because of ease

of administration

RESULTS

• Supplemental insulin in OHA group– Conversion rate from OHA to insulin was very low

in the studies using glyburide 4% in the study by Langer et al

– The conversion rate was higher in studies using metformin 46.3% in the study by Rowan et al

COMMENT

• Postprandial glucose levels are directly related to the risk of fetal macrosomia and adverse pregnancy outcome

• management of gestational diabetes is aimed at dietary manipulation plus supplementary insulin to achieve postprandial glucose targets

• there was no significant difference in postprandial glucose control between insulin and OHAs

COMMENT

• These findings are in accordance with the findings of Nicholson et al who conducted a review of observational studies and randomized trials and found no substantial maternal or neonatal outcome differences with the use of oral hypoglycemic agents in gestational diabetes

COMMENT

• neonatal hypoglycemia secondary to placental transfer appear to be unfounded as similar rates were seen in insulin and OHA users

• This study did not find any differences in congenital anomalies in the 2 groups