Safety of GLP-1 receptor agonists in type 1 diabetes: a systematic review and meta-analysis

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly explored as adjuncts in Type 1 Diabetes Mellitus (T1DM), though concerns regarding hypoglycaemia and diabetic ketoacidosis (DKA) limit their adoption. To comprehensively evaluate their safety, we conducted a systematic review and meta-analysis following PRISMA guidelines. Major databases were searched through June 2025. Outcomes included hypoglycaemia, DKA, gastrointestinal adverse events, and study withdrawals. Twenty-five studies (23 RCTs, 2 observational) were included. Updated pooled data established a neutral risk for overall hypoglycaemia (RR 1.01; Moderate certainty) and serious adverse events (RR 0.89; Moderate certainty). Furthermore, no significant increase was observed for severe hypoglycaemia (RR 0.74; Low certainty) or DKA (RR 0.60; Very Low certainty), though statistical imprecision warrants cautious interpretation. However, GLP-1 RAs significantly increased nausea (RR 2.89) and vomiting (RR 3.10), driving a twofold increase in early treatment withdrawal (RR 2.02; Moderate certainty). Subgroup analysis revealed that overall tolerability significantly improves after six months of therapy. In conclusion, in pooled analyses, GLP-1 RAs were not associated with increased severe hypoglycaemia or DKA, although evidence remains limited. However, a substantial early gastrointestinal burden necessitates cautious patient selection and stepwise dose-titration to maximize patient tolerability and long-term adherence.