Adjunctive glucose-lowering agents in children with type 1 diabetes: a systematic review and meta-analysis

Kun Hu; Sophie Beese; David Moore; Andrew Gan; Rocco Sheldon; Koh Min Dee; Lucy McClean; Brian Mintah; Ananya Mathur; Jiayu Gu; Renuka Dias; Parth Narendran; Timothy Barrett

doi:10.1530/endoabs.111.P98

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Endocrine Abstracts (2025) 111 P98 | DOI: 10.1530/endoabs.111.P98

BSPED2025 Poster Presentations Diabetes 5 (10 abstracts)

Adjunctive glucose-lowering agents in children with type 1 diabetes: a systematic review and meta-analysis

Kun Hu , Sophie Beese , David Moore , Andrew Gan , Rocco Sheldon , Min Dee Koh , Lucy McClean , Brian Mintah , Ananya Mathur , Jiayu Gu , Renuka Dias , Parth Narendran & Timothy Barrett

Author affiliations

University of Birmingham, Birmingham, United Kingdom

Background: Adjunctive non-insulin glucose-lowering agents may offer additional glycaemic benefits in children with established type 1 diabetes (T1D), but evidence supporting their routine use remains limited. This systematic review and meta-analysis aimed to assess their efficacy and safety in paediatric T1D management.

Methods: We searched Medline, Embase, CENTRAL, ClinicalTrials.gov, and WHO ICTRP for English-language randomised control trials from 1946 to 12 March 2024 (PROSPERO: CRD42024512564). Eligible studies included children (≤ 18 years) with T1D duration >3 months, comparing adjunctive non-insulin glucose-lowering agents with usual care, placebo, or another glucose-lowering agent, with ≥12 weeks of treatment. Key efficacy outcomes included changes in HbA1c, total daily insulin dose (TDD), and safety outcomes included rates of hypoglycaemia and diabetic ketoacidosis (DKA). Data were pooled using a random-effects model.

Results: From 5384 records, 31 studies (n = 1510) met inclusion criteria. Meta-analysis showed a significant reduction in HbA1c (%) at 3 months with adjunctive metformin (Mean Difference [MD] -0.31, 95% CI -0.61 to -0.02), in studies with a mean age 12.8–16.9 years, receiving 1000–2000 mg/day. Single study results showed omega-3 fatty acids (MD=-0.3, 95% CI=-0.52 to -0.08), and carnosine (MD -0.90, 95% CI -1.72 to -0.08) also reduced HbA1c (%) at 3 months. Significantly reduced TDD (unit/kg/day) was seen with metformin at both 3 months (MD=-0.12, 95% CI=-0.18 to -0.06, I²=41%) and 6 months (MD=-0.15, 95% CI=-0.23 to -0.06, I²=42%). Sulphonylureas (MD=-0.21, 95% CI=-0.39 to -0.03), omega-3 fatty acids (MD=-0.10, 95% CI= -0.15, -0.05), and thiamine (MD=-0.14, 95% CI=-0.27, -0.01) also reduced TDD. No significant increase in adverse events, hypoglycaemia, or DKA was observed. However, 68% of studies had some concern or high risk of bias (Cochrane RoB2).

Conclusion: Certain adjunctive agents, such as metformin, may reduce HbA1c (%) by up to -0.31% and TDD by up to -0.21 unit/kg/day in children with T1D without increasing adverse events. However, these findings may not be considered significant for clinical practice and are limited by study quality and heterogeneity, such as missing outcome data. Further high-quality trials are needed, particularly evaluating promising newer agents, such as GLP-1 receptor agonists.