Efficacy and Safety of Dulaglutide 3.0 mg and 4.5 mg Versus Dulaglutide 1.5 mg in Metformin-Treated Patients With Type 2 Diabetes in a Randomized Controlled Trial (AWARD-11)
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OBJECTIVE: To compare efficacy and safety of dulaglutide at doses of 3.0 and 4.5 mg versus 1.5 mg in patients with type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODS: Patients were randomly assigned to once-weekly dulaglutide 1.5 mg, 3.0 mg, or 4.5 mg for 52 weeks. The primary objective was determining superiority of dulaglutide 3.0 mg and/or 4.5 mg over 1.5 mg in HbA1c reduction at 36 weeks. Secondary superiority objectives included change in body weight. Two estimands addressed efficacy objectives: treatment regimen (regardless of treatment discontinuation or rescue medication) and efficacy (on treatment without rescue medication) in all randomly assigned patients. RESULTS: Mean baseline HbA1c and BMI in randomly assigned patients (N = 1,842) was 8.6% (70 mmol/mol) and 34.2 kg/m2, respectively. At 36 weeks, dulaglutide 4.5 mg provided superior HbA1c reductions compared with 1.5 mg (treatment-regimen estimand: −1.77 vs. −1.54% [−19.4 vs. −16.8 mmol/mol], estimated treatment difference [ETD] −0.24% (−2.6 mmol/mol), P < 0.001; efficacy estimand: −1.87 vs. −1.53% [−20.4 vs. −16.7 mmol/mol], ETD −0.34% (−3.7 mmol/mol), P < 0.001). Dulaglutide 3.0 mg was superior to 1.5 mg for reducing HbA1c, using the efficacy estimand (ETD −0.17% [−1.9 mmol/mol]; P = 0.003) but not the treatment-regimen estimand (ETD −0.10% [−1.1 mmol/mol]; P = 0.096). Dulaglutide 4.5 mg was superior to 1.5 mg for weight loss at 36 weeks for both estimands (treatment regimen: −4.6 vs. −3.0 kg, ETD −1.6 kg, P < 0.001; efficacy: −4.7 vs. −3.1 kg, ETD −1.6 kg, P < 0.001). Common adverse events through 36 weeks included nausea (1.5 mg, 13.4%; 3 mg, 15.6%; 4.5 mg, 16.4%) and vomiting (1.5 mg, 5.6%; 3 mg, 8.3%; 4.5 mg, 9.3%). CONCLUSIONS: In patients with type 2 diabetes inadequately controlled by metformin, escalation from dulaglutide 1.5 mg to 3.0 mg or 4.5 mg provided clinically relevant, dose-related reductions in HbA1c and body weight with a similar safety profile.
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The recent introduction of higher dulaglutide doses (in 2021) may explain their limited uptake.
“Additionally, the recent introduction of higher dulaglutide doses (in 2021) may explain their limited uptake. 37”
From Real‐world persistence and dose titration of <scp>GLP</scp> ‐1 receptor agonists in type 2 diabetes: A <scp>UK</scp> population‐based cohort study by obesity and cardiovascular disease status (2026) · cites this paper as [37]
The Conclusions (page unavailable) state that the 3.0- and 4.5-mg doses had been approved as additional dosing options, supporting their introduction. The paper does not date that introduction to 2021 or discuss uptake, so it cannot support the proposed explanation for limited uptake. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe incidence of GI adverse effects with tirzepatide appears similar to the GI adverse effects reported with GLP-1 receptor agonists.
“The incidence of GI adverse effects with tirzepatide appears to be similar to the GI adverse effects reported by patients in clinical trials for GLP-1 receptor agonists.”
From Tirzepatide: Clinical review of the twincretin injectable (2023) · cites this paper as [36]
The Results > Safety section (Table 2; page not provided) reports gastrointestinal adverse-effect rates for dulaglutide, a GLP-1 receptor agonist. The paper does not report tirzepatide adverse-effect rates or compare them with dulaglutide, so it supports the GLP-1 comparator data but not the claimed similarity. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHigher-dose GLP-1 RA studies indicate incremental benefits for glucose and weight at higher doses, with greater proportions of people achieving glycemic targets and stepwise dose escalation improving gastrointestinal tolerability.
“The recent higher-dose GLP-1 RA studies have indicated incremental bene fi ts for glucose and weight at higher doses of GLP-1 RA, with greater proportions of people achieving glycemic targets and the ability of stepwise dose escalation to improve gastrointestinal tolerability.”
In AWARD-11, dulaglutide 4.5 mg weekly compared with 1.5 mg weekly demonstrated superior HbA1c reductions and weight loss at 36 weeks in people with type 2 diabetes inadequately controlled with metformin.
“The Assessment of Weekly Administration of LY2189265 (dulaglutide) in Diabetes 11 (AWARD-11) trial evaluated higher doses of dulaglutide (3.0 mg and 4.5 mg weekly) compared with 1.5 mg weekly, demonstrating superior HbA1c reductions ( 19.4 vs. 16.8 mmol/mol [ -1.77 vs. 1.54%], estimated treatment difference [ETD] -2.6 mmol/mol [ 0.24%]) and weight loss ( -4.6 vs. -3.0 kg, ETD -1.6 kg) with d”
In T2DM poorly controlled by metformin, increasing DUL from 1.5 mg to 3.0 mg or 4.5 mg provides glycosylated hemoglobin and weight loss related to clinically relevant doses with similar safety.
“In patients with T2DM who are poorly controlled by metformin, increasing DUL from 1.5mg to 3.0mg or 4.5mg can provide glycosylated hemoglobin and weight loss related to clinically relevant doses and has similar safety (111).”
From GLP−1 receptor agonists for the treatment of obesity: Role as a promising approach (2023) · cites this paper as [111]
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“Dulaglutide is administered subcutaneously at 0.75–1.5 mg once weekly, with doses up to 4.5 mg approved in some regions [17].”
Influential
- Authors
- Frias, J. P., Bonora, E., Nevarez Ruiz, L., Li, Y. G., Yu, Z., Milicevic, Z., Malik, R., Bethel, M. A., & Cox, D. A.
- Affiliations
- National Research Institute, Los Angeles, CA
- University of Verona (IT)
- Hospital Angeles Chihuahua, Chihuahua, Mexico
- Eli Lilly (United States) (US)
- Eli Lilly and Company, Indianapolis, IN
- Corresponding author
- Cox, David A.
- ORCID
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2021-01-04
- Volume
- 44
- Issue
- 3
- Pages
- 765-773
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC7896253
- OpenAlex
- W3119307884
- Cited by
- 199
- References
- 18
- Citations by year
- 2026: 29 · 2025: 46 · 2024: 30 · 2023: 39 · 2022: 23 · 2021: 31 · 2020: 1
- FWCI
- 22.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes Care (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- dulaglutide, type 2 diabetes, metformin, dose comparison, HbA1c reduction, glycemic control, weight loss, GLP-1 receptor agonists, body weight, hypoglycemia, nausea, gastrointestinal adverse effects, drug safety, treatment discontinuation
- MeSH terms
- Diabetes Mellitus, Type 2, Double-Blind Method, Drug Therapy, Combination, Glucagon-Like Peptides, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Immunoglobulin Fc Fragments, Metformin, Recombinant Fusion Proteins, Treatment Outcome
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