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 including standard deviation (p=0.005), mean amplitude of glycemic excursions (p=0.013), time above range (p=0.039), and time in range (p=0.031). 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

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)?

Data extraction

We asked a large language model to extract each data column below from each paper:

• GLP-1 Agonist Comparison:

  • Dulaglutide dose (e.g., 0.75 mg, 1.5 mg weekly)
  • Comparator GLP-1 agonist name and dose (e.g., semaglutide 0.5 mg weekly, liraglutide 1.8 mg daily, exenatide 10 μg twice daily)
  • Administration frequency for both drugs
  • Treatment duration in the study

• HbA1c Efficacy Results:

  • Baseline HbA1c levels for each group
  • Absolute HbA1c change from baseline for dulaglutide group
  • Absolute HbA1c change from baseline for comparator GLP-1 agonist group
  • Between-group difference in HbA1c change (mean difference with 95% CI if available)
  • Time point of assessment (e.g., 26 weeks, 52 weeks)
  • Statistical significance (p-value)
  • Which drug showed superior HbA1c reduction

• Postprandial Glucose Control:

  • Postprandial glucose measurements (2-hour post-meal glucose, glucose excursions, etc.)
  • Glucose variability metrics from continuous glucose monitoring
  • Postprandial insulin or C-peptide responses
  • Time-in-range data if available
  • Between-group differences in postprandial control measures
  • Which drug showed superior postprandial glucose control

• Study Population:

  • Sample size in each treatment group
  • Mean age and diabetes duration
  • Baseline BMI/weight
  • Concomitant diabetes medications (metformin, insulin, etc.)
  • Inclusion/exclusion criteria relevant to GLP-1 agonist comparison
  • Prior GLP-1 agonist experience if mentioned

• Study Design:

  • Study methodology factors relevant to interpreting GLP-1 agonist comparative effectiveness, including:
    • Study design (RCT, observational cohort, post-hoc analysis, meta-analysis)
    • Randomization and blinding status
    • Primary vs secondary analysis
    • Follow-up duration and completion rates
    • Funding source (manufacturer-sponsored vs independent)

• Effect Size Significance:

  • Statistical measures of the magnitude and significance of differences between dulaglutide and other GLP-1 agonists for efficacy outcomes, including:
    • Statistical test used for comparisons
    • P-values for between-group differences
    • Confidence intervals for effect estimates
    • Whether non-inferiority or superiority was demonstrated
    • Clinical significance assessment by authors (if provided)
    • Any subgroup analyses showing differential effects

Results

Characteristics of Included Studies

This review included 10 sources examining dulaglutide compared to other GLP-1 receptor agonists. Three sources provided full text data, while seven were available only as abstracts. The evidence base comprised six primary randomized controlled trials, three meta-analyses or systematic reviews, and one post-hoc pooled analysis.

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. In the AWARD-1 trial comparing dulaglutide to exenatide, dulaglutide 1.5 mg and 0.75 mg showed greater reductions in premeal and postprandial glucose levels compared to both placebo and exenatide. However, for 2-hour postprandial glucose excursions, exenatide demonstrated a greater reduction compared to dulaglutide. Meal-specific analyses revealed dulaglutide 1.5 mg and 0.75 mg achieved greater postprandial glucose reductions at midday and evening meals compared to exenatide.

The Omachi et al. prospective study assessed glucose variability using continuous glucose monitoring. Semaglutide 0.5 mg reduced postprandial hyperglycemia across all meals more effectively than dulaglutide 0.75 mg. Multiple glucose variability metrics favored semaglutide: standard deviation (SD) improved with p=0.005, mean amplitude of glycemic excursions (MAGE) with p=0.013, coefficient of variation (%CV) with p=0.038, time above range (TAR) with p=0.039, and time in range (TIR) with p=0.031. The study concluded that semaglutide improved glucose variability more efficiently than dulaglutide by reducing postprandial hyperglycemia.