Dulaglutide vs other GLP-1 receptor agonists: differences in efficacy for HbA1c and postprandial glucose control?

Abstract

Dulaglutide demonstrates non-inferior to superior HbA1c efficacy compared to other GLP-1 receptor agonists, with the magnitude of benefit varying by comparator. Dulaglutide 1.5 mg weekly was non-inferior to liraglutide 1.8 mg daily (-1.42% vs -1.36% HbA1c reduction), though meta-analysis of six studies suggested small superiority favoring dulaglutide at 6 months (-0.17%, 95% CI -0.26 to -0.08) and 12 months (-0.22%, 95% CI -0.32 to -0.11). Against exenatide 10 μg twice daily, dulaglutide showed consistent superiority with 0.4-0.6% greater HbA1c reductions at both 26 and 52 weeks (P<0.001). Compared to semaglutide, dulaglutide 1.5 mg achieved similar glycemic control to semaglutide 0.5 mg, though semaglutide demonstrated superiority when initiated in patients already receiving stable dulaglutide therapy (-0.4% vs +0.2%, p=0.006).

Postprandial glucose control data were limited, with only two studies providing specific assessments. Dulaglutide showed greater reductions in premeal and postprandial glucose levels than exenatide at midday and evening meals, though exenatide achieved superior 2-hour postprandial glucose excursion reduction. Semaglutide reduced postprandial hyperglycemia across all meals more effectively than dulaglutide and improved multiple glucose variability metrics. The comparative efficacy hierarchy appears influenced by dose selection, with dulaglutide 1.5 mg consistently outperforming 0.75 mg, and by pharmacokinetic differences between rapid-acting, intermediate-acting, and long-acting GLP-1 receptor agonists.

Methods

We analyzed 10 sources from an initial pool of 200, using 6 screening criteria. Each paper was reviewed for 6 key aspects that mattered most to the research question.

Records from Elicit search
n = 200
Papers screened using: Population Age and Diabetes Type, Study Comparison, Efficacy Outcomes, Study Design, Study Duration, Drug Administration
n = 200
Papers screened out
n = 190
Papers included for extraction
n = 10

Screening

We screened in sources based on their abstracts that met these criteria:

• Population Age and Diabetes Type: Does this study include adults (≥18 years) with type 2 diabetes mellitus (and exclude patients with type 1 diabetes or gestational diabetes)?
• Study Comparison: Does this study compare dulaglutide directly with at least one other GLP-1 receptor agonist?
• Efficacy Outcomes: Does this study report HbA1c levels and/or postprandial glucose measurements?
• Study Design: Is this study a randomized controlled trial, systematic review, or meta-analysis (and not a preclinical study, in vitro study, animal study, case report, case series, or editorial)?
• Study Duration: Does this study have a minimum follow-up duration of 12 weeks or longer?
• Drug Administration: Is dulaglutide used as a single GLP-1 receptor agonist (not in combination with other GLP-1 receptor agonists)?

HbA1c Efficacy

Dulaglutide versus Liraglutide

Direct head-to-head comparison in the AWARD-6 trial demonstrated non-inferiority of dulaglutide 1.5 mg weekly to liraglutide 1.8 mg daily. The least-squares mean HbA1c reduction was -1.42% for dulaglutide compared to -1.36% for liraglutide, with a between-group difference of -0.06% (95% CI -0.19 to 0.07, p<0.0001 for non-inferiority). Non-inferiority was established using a 0.4% margin.

The meta-analysis by Ye et al. including three RCTs and three observational studies found dulaglutide superior to liraglutide for HbA1c reduction at 6 months (mean difference -0.17%, 95% CI -0.26 to -0.08) and 12 months (-0.22%, 95% CI -0.32 to -0.11).

Dulaglutide versus Exenatide

Dulaglutide demonstrated superior HbA1c reduction compared to twice-daily exenatide across multiple studies. In the AWARD-1 trial, dulaglutide 1.5 mg reduced HbA1c by -1.51% versus -0.99% for exenatide 10 μg at 26 weeks, with superiority maintained at 52 weeks (-1.36% vs -0.80%, between-group difference -0.56%, P<0.001).

Dulaglutide versus Semaglutide

Three analyses from the SUSTAIN 7 trial compared semaglutide to dulaglutide. The prospective study by Omachi et al. demonstrated semaglutide 0.5 mg superiority over dulaglutide 0.75 mg in a population already treated with dulaglutide.

Summary Table of HbA1c Efficacy

Postprandial Glucose Control

Postprandial glucose control data were limited across the included studies. Most trials focused on HbA1c as the primary glycemic outcome without reporting specific postprandial measurements. Two studies provided postprandial-specific data indicating that semaglutide improved glucose variability more effectively than dulaglutide.

References

1. Ye, J., Chang, K., Chen, H. Y. (2020). Effectiveness of Dulaglutide and Liraglutide in Glycemic Control, Weight Loss and Blood Pressure Reduction: A Systematic Review and Meta-Analysis. Value in Health.
2. Gurung, T., Shyangdan, D., O’Hare, J., Waugh, N. (2015). A novel, long-acting glucagon-like peptide receptor-agonist: dulaglutide. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy.
3. Dungan, K., Povedano, S. T., Forst, T., González, J. G., Atisso, C., et al. (2014). Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. The Lancet.
4. Wysham, C., Blevins, T., Arakaki, R., Colon, G., García, P., et al. (2014). Efficacy and Safety of Dulaglutide Added Onto Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1). Diabetes Care.
5. Burness, C. B., Scott, L. (2015). Dulaglutide: A Review in Type 2 Diabetes. BioDrugs.
6. Schmidt, W., Pratley, R., Frias, J., Kumar, H., Petrie, J., et al. (2018). Efficacy of semaglutide vs. dulaglutide across baseline HbA1c in SUSTAIN 7. Diabetologie und Stoffwechsel.
7. Zaccardi, F., Htike, Z. Z., Webb, D., Khunti, K., Davies, M. (2016). Benefits and Harms of Once-Weekly Glucagon-like Peptide-1 Receptor Agonist Treatments. Annals of Internal Medicine.
8. Adetunji, O., Skrivanek, Z., Tahbaz, A., Bain, S., Pechtner, V. (2014). A post-hoc pooled analysis of two placebo-controlled phase 3 trials: dulaglutide compared with exenatide, sitagliptin, and placebo. Diabetologie Und Stoffwechsel.
9. Pratley, R., Aroda, V., Gondolf, T., Hansen, T., Lingvay, I., et al. (2019). Efficacy and Safety of Semaglutide 0.5 mg vs. Dulaglutide 1.5 mg Once Weekly in Type 2 Diabetes: A Post Hoc Analysis of SUSTAIN 7. Diabetes.
10. Omachi, T., Ohara, M., Fujikawa, T., Kohata, Y., Sugita, H., et al. (2023). Comparison of Effects of Injectable Semaglutide and Dulaglutide on Oxidative Stress and Glucose Variability in Patients with Type 2 Diabetes Mellitus: A Prospective Preliminary Study. Diabetes Therapy.