Low-dose glucagon to prevent and treat exercise-associated hypoglycemia in individuals with type 1 diabetes: A systematic review and meta-analysis.

Background: People with type 1 diabetes (T1D) struggle to manage exercise due to hypoglycemia risk. Purpose: This systematic review and meta-analysis evaluated low-dose glucagon's efficacy for preventing and treating exercise-induced hypoglycemia in T1D. Data Sources: MEDLINE, Embase, and Cochrane Central were searched for randomized controlled trials and crossover studies until September 2024. Study Selection: The analysis included T1D adolescents and adults treated with low-dose glucagon versus non-glucagon treatments. Studies with glucagon-like peptides, non-insulin combinations, or uncontrolled exercise settings were excluded. Data extraction: Two authors extracted the data. The methodological quality was assessed with the Risk of Bias-2 tool and GRADE framework. The ROB-2 informed a sensitivity analysis. The meta-analysis employed a random-effects model to estimate the pooled treatment effects on hypoglycemia and Time Below Range (TBR, glucose <3.9 mmol/L), as well as secondary outcomes and adverse effects. Data synthesis: Of 6,792 records, 12 studies involving 248 individuals (mean age: 36 ± 10.5 years) met inclusion criteria. The meta-analysis showed significant reductions in hypoglycemia risk (RR 0.54, CI [0.35-0.84]) and TBR (-3.91 %-point, CI [-6.27;1.54]) with low-dose glucagon. Sensitivity analysis yielded a slightly more confident effect size for hypoglycemia and TBR. However, overall adverse events increased with low-dose glucagon (RR 2.75, CI [1.07;7.08]). Limitations: The included studies were few and heterogeneous, which may have influenced the overall outcomes. Conclusions: Low-dose glucagon reduces exercise-induced hypoglycemia and TBR in T1D individuals. Future research should optimize glucagon dosage and timing for various exercise types and durations to confirm real-world effectiveness.