Clinical Context
Within the GLP-1 receptor agonist class, clinicians and patients have multiple options with varying efficacy, dosing schedules, and side effect profiles. Dulaglutide (Trulicity) and semaglutide (Ozempic) are both once-weekly GLP-1 RAs widely used in type 2 diabetes management. Understanding how these agents compare helps inform treatment selection.
Head-to-head comparisons within drug classes provide crucial information that placebo-controlled trials cannot. While both agents clearly beat placebo, the SUSTAIN 7 trial directly compared semaglutide to dulaglutide to determine whether one provides meaningfully greater efficacy. Such comparisons help clinicians recommend the most effective therapy and inform switching decisions for patients with suboptimal response to initial GLP-1 RA therapy.
The comparison used dose pairings (semaglutide 0.5 mg vs dulaglutide 0.75 mg; semaglutide 1.0 mg vs dulaglutide 1.5 mg) that were considered therapeutically equivalent at the time, allowing assessment of whether true efficacy differences exist or whether observed differences simply reflect dosing.
PICO Summary
Population: Adults with type 2 diabetes (n=1,201), HbA1c 7.0-10.5%, inadequately controlled on metformin alone.
Intervention: Once-weekly semaglutide at 0.5 mg or 1.0 mg for 40 weeks.
Comparison: Once-weekly dulaglutide at 0.75 mg or 1.5 mg for 40 weeks.
Outcome: At both dose comparisons, semaglutide achieved significantly greater HbA1c reduction: 1.5% vs 1.1% (lower doses) and 1.8% vs 1.4% (higher doses), P<0.0001 for both. Weight loss was also significantly greater with semaglutide: 4.6 kg vs 2.3 kg (lower doses) and 6.5 kg vs 3.0 kg (higher doses). More semaglutide patients achieved HbA1c <7.0%. Gastrointestinal adverse events were more frequent with semaglutide.
Clinical Pearls
1. Semaglutide Demonstrates Clear Superiority: At both dose comparisons, semaglutide achieved approximately 0.4% greater HbA1c reduction than dulaglutide. This difference is clinically meaningful—equivalent to adding another diabetes medication. Not all GLP-1 RAs are equivalent; semaglutide appears to be the most potent in the class.
2. Weight Loss Differences Are Substantial: The ~3.5 kg additional weight loss with semaglutide compared to dulaglutide at higher doses (6.5 kg vs 3.0 kg) represents more than doubling of weight reduction. For patients where weight management is a primary goal, this difference strongly favors semaglutide.
3. Higher Efficacy Comes With More GI Effects: Semaglutide’s greater efficacy is accompanied by higher rates of gastrointestinal adverse events (nausea, vomiting, diarrhea). For most patients, these transient effects are acceptable given the efficacy benefits, but some may tolerate dulaglutide better.
4. Target Achievement Favors Semaglutide: More patients on semaglutide achieved HbA1c <7.0%, meaning more patients will reach glycemic goals with semaglutide than dulaglutide. This reduces the need for additional therapy escalation.
Practical Application
When selecting a once-weekly GLP-1 RA, semaglutide should generally be preferred over dulaglutide based on superior glycemic efficacy and weight loss. The magnitude of differences (0.4% additional HbA1c reduction, 3.5 kg additional weight loss) justify starting with the more effective agent.
Consider dulaglutide when: semaglutide causes intolerable GI effects, cost or formulary restrictions favor dulaglutide, or patients specifically prefer the dulaglutide delivery device (single-use autoinjector). Some patients who fail semaglutide due to GI intolerance may tolerate dulaglutide, though efficacy will be lower.
For patients already on dulaglutide with suboptimal response, switching to semaglutide can provide additional glycemic and weight benefits. This intra-class switch is reasonable before adding additional drug classes, given semaglutide’s demonstrated superiority.
Broader Evidence Context
SUSTAIN 7 is the largest head-to-head GLP-1 RA comparison trial. The results align with cross-trial comparisons suggesting semaglutide’s position at the top of the GLP-1 RA efficacy hierarchy. Similar superiority patterns have been demonstrated against exenatide ER (SUSTAIN 3) and sitagliptin (SUSTAIN 2).
The cardiovascular outcome trials for both agents showed benefit (SUSTAIN-6 for semaglutide; REWIND for dulaglutide), supporting either choice for cardiometabolic protection. However, semaglutide’s additional SELECT trial demonstrated CV benefit even in non-diabetic obesity.
Study Limitations
The open-label design may have influenced adherence and reporting of subjective outcomes. The dose pairings reflected 2018 understanding of therapeutic equivalence; dulaglutide 3.0 mg and 4.5 mg doses have since become available but weren’t compared. The trial didn’t assess cardiovascular or other long-term outcomes.
Bottom Line
Semaglutide provides significantly greater HbA1c reduction and weight loss compared to dulaglutide at both dose comparisons tested. The approximately 0.4% additional HbA1c reduction and 3.5 kg additional weight loss establish semaglutide as the more effective once-weekly GLP-1 RA option for most patients with type 2 diabetes.
Source: Pratley RE, et al. “Semaglutide Versus Dulaglutide Once Weekly in Patients with Type 2 Diabetes (SUSTAIN 7): A Randomised, Open-Label, Phase 3b Trial.” Lancet Diabetes & Endocrinology, 2018;6(4):275-286. Read article
