Glucagon-like peptide-1 receptor agonists as add-on therapy to insulin for type 1 diabetes mellitus: a systematic review and meta-analysis

Abstract Aims We conducted a systematic review to compare the efficacy and safety of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) versus placebo in addition to insulin treatment in patients with type 1 diabetes (T1D). Methods We searched the PubMed and Cochrane databases up to November, 2023. Randomized controlled trials (RCTs) with a duration of ≥ 12 weeks were deemed eligible for the primary outcome (change in HbA 1c ) and change in body weight. RCTs with a duration of ≥ 4 weeks were deemed eligible for the incidence of severe hypoglycemia, time-in-range (TIR), total insulin dose (TID), change in C-peptide, and glucagon levels. We calculated mean differences (MDs) for continuous outcomes and odds ratios (ORs) for severe hypoglycemia, alongside 95% CIs using an inverse-variance weighted random-effects model. Results A total of 25 RCTs were eligible. Compared with placebo, use of GLP-1RA was associated with a reduction in HbA 1c (MD -0.23%, 95% CI -0.30, -0.17), body weight (MD -3.93 kg, 95% CI -4.29, -3.56), and TID (MD -5.74 U/day, 95% CI -7.30, -4.19). Addition of GLP-1RAs did not significantly affect time-in-range. Based on data from 13 studies, the odds for severe hypoglycemia were similar between patients receiving GLP1-RA and placebo. Qualitative assessment of individual trials showed that addition of GLP-1RA does not prevent progressive C-peptide loss and that patients receiving a GLP-1RAs do not have inadequate glucagon secretion in response to hypoglycemia. Conclusion The addition of GLP-1RA on top of insulin therapy in people with T1D results in a modest reduction in HbA 1c , body weight, and TID without increasing the risk for severe hypoglycemia.