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Peer-reviewedCC BY-NC-ND 4.0JAMA Network Open

Early Metformin Initiation and Glycemic Outcomes in Gestational Diabetes

  • David Alberto Aguilar Macías1,2,3
  • Alberto Alvarez-Iglesias1,2,3,4
  • John M. Ferguson5
  • Aoife Maria Egan6
  • Paula M. O’Shea3,4,7
  • Declan Devane2,4,8,9
  • Christine Newman1,2,4,10
  • Robert Patrick McEvoy11
  • Mary FitzGerald1,2,3
  • Martin J. O’Donnell1,2,3,10
  • Fidelma F. Dunne1,2,3,4,10
11 affiliations
  1. 1HRB Clinical Research Facility Galway, University of Galway, Galway, Ireland
  2. 2Institute for Clinical Trials, University of Galway, Galway, Ireland
  3. 3College of Medicine, Nursing and Health Sciences, University of Galway, Galway, Ireland
  4. 4National Clinical Trial Network Diabetes, Galway, Ireland
  5. 5School of Mathematical and Statistical Sciences, University of Galway, Galway, Ireland
  6. 6Department of Endocrinology, Mayo Clinic, Rochester, Minnesota
  7. 7Department of Clinical Biochemistry and Diagnostic Endocrinology, The Mater Misericordiae University Hospital, Dublin, Ireland
  8. 8Health Research Board, Trials Methodology Research Network, University of Galway, Galway, Ireland
  9. 9School of Nursing and Midwifery, University of Galway, Galway, Ireland
  10. 10Department of Medicine, Galway University Hospital, Galway, Ireland
  11. 11Centre for Diabetes, Endocrinology and Research, Cork University Hospital, Cork, Ireland
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Abstract

Importance: Conventional approaches to analyzing composite end points in clinical trials may not fully capture clinically meaningful treatment effects.

Objective: To estimate treatment effects of early metformin initiation on clinically ordered glycemic outcomes (insulin initiation and fasting hyperglycemia at gestational weeks 32 and 38) using generalized pairwise comparisons (GPCs).

Design, Setting, and Participants: This secondary analysis of a double-masked, placebo-controlled randomized clinical trial (conducted from June 2017 through September 2022) at 2 centers in Ireland (1 tertiary hospital and 1 regional hospital) included participants with gestational diabetes based on World Health Organization 2013 criteria. Participants were followed up through 12 weeks post partum. The data analysis was performed between October 18, 2025, and February 2, 2026.

Intervention: Participants were randomized 1:1 to metformin (maximum dose, 2500 mg) or matching placebo, in addition to usual care.

Main Outcomes and Measures: Generalized pairwise comparisons were performed using (1) a prioritized hierarchy (insulin initiation, fasting hyperglycemia at week 32, and fasting hyperglycemia at week 38) and (2) nonprioritized analyses of each end point, with overall summaries using equal weights and prespecified clinical weights (0.50, 0.25, and 0.25, respectively). Treatment effect sizes were summarized using win ratio (WR), net treatment benefit (NTB), and win odds (WO).

Results: Of 535 randomized pregnancies, 526 (262 placebo [49.0%] and 264 metformin [51.0%]; mean [SD] age of participants, 34.4 [4.8] years) had primary outcome data. Prioritized GPCs favored metformin over placebo for the composite outcome (WR, 1.46 [95% CI, 1.13-1.89]; NTB, 13.7 percentage points [95% CI, 4.3-22.8 percentage points]; WO, 1.34 [95% CI, 1.10-1.64]) ( P = .004). The largest separation was observed for insulin initiation (WR, 1.68 [95% CI, 1.19-2.38]; NTB, 12.7 percentage points [95% CI, 4.2-21.0 percentage points]) ( P = .003). Nonprioritized overall summaries favored metformin (WR, 1.53 [95% CI, 1.16-2.01]; NTB, 7.5 percentage points [95% CI, 2.7-12.3 percentage points]; WO, 1.32 [95% CI, 1.10-1.57]) ( P = .002), with consistent clinically weighted results (WR, 1.57 [95% CI, 1.19-2.08]; NTB, 8.8 percentage points [95% CI, 3.4-14.2 percentage points]; WO, 1.39 [95% CI, 1.14-1.70]) ( P = .001).

Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, prioritized and nonprioritized GPCs yielded statistically significant overall estimates favoring early metformin initiation over placebo across insulin initiation and fasting hyperglycemia outcomes. These findings complement the original primary analysis, provide a more clinically interpretable assessment of the composite outcome, and may inform prospective end point design in future trials.

Trial Registration: ClinicalTrials.gov Identifier: NCT02980276 ; EudraCT: 2016-001644-19

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Cite

BibTeXRIS
BibTeX
@article{macias2026early,
  title = {{Early Metformin Initiation and Glycemic Outcomes in Gestational Diabetes}},
  author = {David Alberto Aguilar Macías and Alberto Alvarez-Iglesias and John M. Ferguson and Aoife Maria Egan and Paula M. O’Shea and Declan Devane and Christine Newman and Robert Patrick McEvoy and Mary FitzGerald and Martin J. O’Donnell and Fidelma F. Dunne},
  journal = {JAMA Network Open},
  year = {2026},
  month = nov,
  doi = {10.1001/jamanetworkopen.2026.35700},
  url = {https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2856230},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Early Metformin Initiation and Glycemic Outcomes in Gestational Diabetes
AU  - David Alberto Aguilar Macías
AU  - Alberto Alvarez-Iglesias
AU  - John M. Ferguson
AU  - Aoife Maria Egan
AU  - Paula M. O’Shea
AU  - Declan Devane
AU  - Christine Newman
AU  - Robert Patrick McEvoy
AU  - Mary FitzGerald
AU  - Martin J. O’Donnell
AU  - Fidelma F. Dunne
PY  - 2026
DA  - 2026/11/03
JO  - JAMA Network Open
DO  - 10.1001/jamanetworkopen.2026.35700
UR  - https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2856230
AB  - Importance: Conventional approaches to analyzing composite end points in clinical trials may not fully capture clinically meaningful treatment effects.  Objective: To estimate treatment effects of early metformin initiation on clinically ordered glycemic outcomes (insulin initiation and fasting hyperglycemia at gestational weeks 32 and 38) using generalized pairwise comparisons (GPCs).  Design, Setting, and Participants: This secondary analysis of a double-masked, placebo-controlled randomized clinical trial (conducted from June 2017 through September 2022) at 2 centers in Ireland (1 tertiary hospital and 1 regional hospital) included participants with gestational diabetes based on World Health Organization 2013 criteria. Participants were followed up through 12 weeks post partum. The data analysis was performed between October 18, 2025, and February 2, 2026.  Intervention: Participants were randomized 1:1 to metformin (maximum dose, 2500 mg) or matching placebo, in addition to usual care.  Main Outcomes and Measures: Generalized pairwise comparisons were performed using (1) a prioritized hierarchy (insulin initiation, fasting hyperglycemia at week 32, and fasting hyperglycemia at week 38) and (2) nonprioritized analyses of each end point, with overall summaries using equal weights and prespecified clinical weights (0.50, 0.25, and 0.25, respectively). Treatment effect sizes were summarized using win ratio (WR), net treatment benefit (NTB), and win odds (WO).  Results: Of 535 randomized pregnancies, 526 (262 placebo [49.0%] and 264 metformin [51.0%]; mean [SD] age of participants, 34.4 [4.8] years) had primary outcome data. Prioritized GPCs favored metformin over placebo for the composite outcome (WR, 1.46 [95% CI, 1.13-1.89]; NTB, 13.7 percentage points [95% CI, 4.3-22.8 percentage points]; WO, 1.34 [95% CI, 1.10-1.64]) ( P = .004). The largest separation was observed for insulin initiation (WR, 1.68 [95% CI, 1.19-2.38]; NTB, 12.7 percentage points [95% CI, 4.2-21.0 percentage points]) ( P = .003). Nonprioritized overall summaries favored metformin (WR, 1.53 [95% CI, 1.16-2.01]; NTB, 7.5 percentage points [95% CI, 2.7-12.3 percentage points]; WO, 1.32 [95% CI, 1.10-1.57]) ( P = .002), with consistent clinically weighted results (WR, 1.57 [95% CI, 1.19-2.08]; NTB, 8.8 percentage points [95% CI, 3.4-14.2 percentage points]; WO, 1.39 [95% CI, 1.14-1.70]) ( P = .001).  Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, prioritized and nonprioritized GPCs yielded statistically significant overall estimates favoring early metformin initiation over placebo across insulin initiation and fasting hyperglycemia outcomes. These findings complement the original primary analysis, provide a more clinically interpretable assessment of the composite outcome, and may inform prospective end point design in future trials.  Trial Registration: ClinicalTrials.gov Identifier: NCT02980276 ; EudraCT: 2016-001644-19
SN  - 2574-3805
ER  -