Comparative Efficacy and Safety of Weekly GLP-1/GIP Agonists vs. Weekly Insulin in Type 2 Diabetes: A Network Meta-Analysis of Randomized Controlled Trials

Abstract

Background: Diabetes mellitus (DM) significantly impacts global health due to its complications and the economic burden it places on healthcare systems. The rise of novel once-weekly diabetes medications with different mechanisms of action necessitates an evaluation of their relative efficacy and safety.

Objectives: This study compares the efficacy and tolerability of once-weekly insulin analogs (icodec and BIF) with once-weekly GLP-1/GIP agonists (semaglutide, exenatide, tirzepatide, dulaglutide) in managing type 2 diabetes mellitus (T2DM).

Methods: We conducted a network meta-analysis (NMA) using data from randomized controlled trials (RCTs) that compared these treatments with a baseline of daily basal insulin. Primary outcomes included changes in HbA1c, body weight, and tolerability.

Results: The analysis integrated data from 25 RCTs, involving 18,257 patients. Tirzepatide significantly outperformed other treatments in reducing HbA1c and promoting weight loss. Weekly insulins, compared to GLP-1/GIP agonists, showed a more tolerable profile and were beneficial for certain patient demographics emphasizing weight stability.

Conclusion: Our findings suggest that while once-weekly GLP-1/GIP agonists provide superior glycemic control and weight management, weekly insulins offer viable options for patients prioritizing fewer side effects and weight stability. This comprehensive comparison aids in refining personalized treatment strategies for T2DM management.

Keywords: GLP-1/GIP receptor agonists; HbA1c reduction; diabetes management; once-weekly insulin; treatment tolerability.

Figure 1

PRISMA flowchart for study selection.

Figure 2

Meta-analysis networks for change in HbA1c level. Each circle indicates a treatment node. Lines connecting two nodes represent direct comparisons between two treatments; the thickness of the lines is proportional to the number of trials directly comparing the two connected treatments.

Figure 3

Network meta-analysis results for change from baseline. HbA1c compared with daily insulin. Effect sizes are presented as mean difference (MD) and 95% confidence intervals (CI). Treatments are presented according to their effect estimate compared with glargine. Abbreviations: HbA1c: hemoglobin A1c, BIF: basal insulin Fc.

Figure 4

The surface under the cumulative ranking (SUCRA) plot displays the ranking probabilities of treatments in reducing hemoglobin A1c (HbA1c). Higher SUCRA scores indicate a greater likelihood of lowering HbA1c. Abbreviations: T3: tirzepatide 15 mg, T2: tirzepatide 10 mg, T1: tirzepatide 5 mg, S3: semaglutide 2 mg, S2: semaglutide 1 mg, S1: semaglutide 0.5 mg, D2: dulaglutide 1.5 mg, E: exenatide 2 mg, I: icodec, D: daily insulin, B: BIF, D1: dulaglutide 0.75 mg.

Figure 5

(A) Network meta-analysis results for change from baseline in FPG compared with daily insulin. (B). Network meta-analysis results for change from baseline in weight compared with daily insulin. Effect sizes are presented as mean difference (MD) and 95% confidence intervals (CI). Treatments are presented according to their effect estimate compared with daily insulin. Abbreviations: FPG: fasting plasma glucose, BIF: basal insulin Fc.

Figure 6

(A) Network meta-analysis results for change from baseline in pooled hypoglycemia. (B) Network meta-analysis results for change from baseline in level 2 (≤55 mg/dL) hypoglycemia. Effect sizes are presented as risk ratio (RR) and 95% confidence intervals (CI). Treatments are presented according to their effect estimate compared with daily insulin. Abbreviations: BIF: basal insulin Fc.

Figure 7

Network meta-analysis results for (A) incidence in adverse events. (B) incidence in serious adverse events. (C) treatment discontinuation due to adverse events compared with daily insulin. Treatments are presented according to their effect estimate compared with daily insulin. Effect sizes are presented as risk ratio (RR) and 95% confidence intervals (CI). Abbreviations: BIF: basal insulin Fc.