Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists as Adjuncts to Insulin Therapy in Type 1 Diabetes Mellitus: An Overlap-Informed Umbrella Review

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Abstract

AIM: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as potential adjuncts to insulin therapy for type 1 diabetes mellitus (T1DM). However, interpretation of the available evidence is complicated by substantial primary-study overlap, methodological heterogeneity and variable certainty of evidence. Thus, we conducted an overlap-informed umbrella review to evaluate the efficacy and safety of GLP-1RAs as adjunctive therapy in T1DM. MATERIALS AND METHODS: We searched PubMed/MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and OpenAlex from inception to 22 June 2026, and manually screened reference lists to identify systematic reviews with meta-analyses that included randomized controlled trials (RCTs), either alone or alongside nonrandomized studies, evaluating adjunctive GLP-1RA therapy in T1DM. Methodological quality was assessed using AMSTAR 2, and primary-study overlap was quantified using a citation matrix and corrected covered area (CCA). Outcome-specific representative meta-analyses were selected, and their primary-study data were independently reanalyzed using random-effects models. Continuous and dichotomous outcomes were summarized as mean differences (MDs) and risk ratios (RRs), respectively, with 95% confidence intervals (CIs). The certainty of evidence was assessed using GRADE. RESULTS: Eighteen systematic reviews with meta-analyses encompassing 56 unique primary studies (35 RCTs and 21 nonrandomized studies) were included. The calculated CCA was 19.6%, indicating a very high degree of primary-study overlap, largely driven by the ADJUNCT ONE and ADJUNCT TWO trials. Adjunctive GLP-1RA therapy reduced HbA1c (MD, -0.23% [95% CI, -0.30 to -0.17]; moderate certainty), body weight (MD, -3.93 kg [-4.29 to -3.56]; moderate certainty) and total daily insulin dose (MD, -5.74 IU/day [-7.30 to -4.17]; low certainty). No significant improvement was observed in time in range (MD, 1.99% [95% CI, -1.17 to 5.15]; very low certainty). No statistically significant increases were observed in severe hypoglycemia (RR, 0.83 [95% CI, 0.36-1.91]; low certainty) or diabetic ketoacidosis (RR, 0.67 [95% CI, 0.16-2.86]; low certainty). However, GLP-1RAs increased the risks of nausea (RR, 2.88 [95% CI, 2.20-3.76]; high certainty), vomiting (RR, 3.11 [1.94-4.97]; high certainty), and withdrawal due to adverse events (RR, 2.10 [1.42-3.12]; high certainty), whereas the risk of diarrhoea was not significantly increased (RR, 1.88 [0.82-4.33]; low certainty). CONCLUSIONS: Adjunctive GLP-1RA therapy was associated with a modest reduction in HbA1c and clinically relevant reductions in body weight and insulin requirements, without a significant improvement in time in range. Gastrointestinal adverse events were increased, whereas the risks of diabetic ketoacidosis and severe hypoglycemia remained uncertain. These findings do not support routine use but suggest a potential role in selected individuals for whom weight reduction and lower insulin requirements are therapeutic priorities.

Abstract as published, via PubMed.