Concerns regarding severe hypoglycemia and diabetic ketoacidosis (DKA) have limited the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as adjunctive therapy in type 1 diabetes mellitus (T1DM). A systematic review and meta-analysis published in Diabetes Research and Clinical Practice found no significant increase in severe hypoglycemia or DKA with GLP-1 RA therapy, although gastrointestinal adverse events and early treatment discontinuation were more frequent.

The PRISMA-guided analysis searched major databases through June 2025 and included 25 studies comprising 23 randomized controlled trials and 2 observational studies. Prespecified outcomes included overall hypoglycemia, severe hypoglycemia, DKA, gastrointestinal adverse events, serious adverse events, and treatment withdrawal.

Pooled analyses showed no increase in overall hypoglycemia risk with GLP-1 RAs compared with control groups (RR, 1.01; moderate certainty). No significant increase was observed for severe hypoglycemia (RR, 0.74; low certainty) or DKA (RR, 0.60; very low certainty), although the DKA estimates were statistically imprecise. Serious adverse event risk was also similar between groups (RR, 0.89; moderate certainty).

In contrast, gastrointestinal adverse events occurred more frequently with GLP-1 RA therapy, including nausea (RR, 2.89) and vomiting (RR, 3.10). Early treatment withdrawal was approximately twofold higher with GLP-1 RAs (RR, 2.02; moderate certainty). Subgroup analyses showed that tolerability improved after 6 months of therapy.

The findings suggest that GLP-1 RAs were not associated with increased severe hypoglycemia or DKA in pooled analyses, although gastrointestinal tolerability remains an important limitation in T1DM.