Low-Dose Glucagon to Prevent and Treat Exercise-Associated Hypoglycemia in Individuals With Type 1 Diabetes: A Systematic Review and Meta-analysis

Abstract

OBJECTIVE People with type 1 diabetes (T1D) struggle to manage exercise because of hypoglycemia risk. RESEARCH DESIGN AND METHODS This systematic review and meta-analysis evaluated low-dose glucagon’s efficacy for preventing and treating exercise-induced hypoglycemia in T1D. Medline, Em-base, and Cochrane CENTRAL were searched for randomized controlled trials and crossover studies until September 2024. The analysis included T1D adolescents and adults treated with low-dose glucagon versus nonglucagon treatments. Studies with glucagon-like peptides, noninsulin combinations, or uncontrolled exercise settings were excluded. Two authors extracted the data. The methodological quality was assessed with the Risk of Bias-2 tool and Grading of Recommendations Assessment, Development and Evaluations framework. Risk of Bias 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. RESULTS Of 6,792 records, 12 studies involving 248 individuals (mean age: 36 6 10.5 years) met inclusion criteria. The meta-analysis showed significant reductions in hypoglycemia risk (risk ratio 0.54; 95% CI 0.35, 0.84) and TBR (23.91 percentage points; 95% CI 26.27, 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 (risk ratio 2.75; 95% CI 1.07, 7.08). 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.