Clinical Context
The development of semaglutide began with early-phase dose-finding studies designed to identify the optimal balance between efficacy and tolerability. This Phase 2 trial represents the foundation of semaglutide’s clinical development program, systematically evaluating multiple doses and dose escalation strategies to inform Phase 3 development.
At the time of this study (2016), liraglutide was the established GLP-1 RA benchmark. Understanding how semaglutide compared to liraglutide was essential for determining whether the new agent offered meaningful advantages. The inclusion of liraglutide as an active comparator, alongside placebo, provided crucial context for interpreting semaglutide’s efficacy.
The study’s dose-ranging design tested doses from 0.1 mg to 1.6 mg weekly, both with and without gradual escalation. This comprehensive approach identified not just effective doses but also the importance of titration in managing gastrointestinal tolerability—insights that directly informed the clinical dosing protocols used today.
PICO Summary
Population: Adults with type 2 diabetes (n=415), HbA1c 7.0-10.0%, on diet and exercise or metformin, body weight 60-110 kg.
Intervention: Once-weekly subcutaneous semaglutide at various doses (0.1 mg, 0.2 mg, 0.4 mg, 0.8 mg, 1.6 mg), with and without dose escalation, for 12 weeks.
Comparison: Weekly placebo (double-blind) and open-label daily liraglutide (1.2 mg or 1.8 mg).
Outcome: Semaglutide produced dose-dependent HbA1c reductions up to 1.7% (at 1.6 mg) versus 0.4% with placebo and 1.2% with liraglutide 1.8 mg. Weight loss reached 4.8 kg with semaglutide 1.6 mg versus 0.9 kg with placebo and 2.1 kg with liraglutide. Gastrointestinal adverse events (nausea, vomiting, diarrhea) were dose-dependent, reduced with gradual escalation.
Clinical Pearls
1. Clear Dose-Response Established Early: From the earliest phase of development, semaglutide demonstrated consistent dose-response relationships for both HbA1c reduction and weight loss. This predictability informed dose selection for Phase 3 trials and clinical practice—higher doses produce greater effects.
2. Superiority Over Liraglutide Evident Early: At comparable efficacy doses, semaglutide outperformed liraglutide for both glycemic control and weight loss. The 1.7% HbA1c reduction with semaglutide 1.6 mg exceeded liraglutide 1.8 mg’s 1.2% reduction—a signal that predicted the consistent superiority seen in subsequent trials.
3. Dose Escalation Reduces GI Adverse Events: Arms with gradual dose escalation showed better GI tolerability than fixed-dose arms. This finding directly informed clinical practice: the standard 4-week escalation steps (0.25 mg → 0.5 mg → 1.0 mg) allow the GI tract to adapt before further dose increases.
4. Weekly Dosing Achieves Sustained Effects: The 12-week duration confirmed that once-weekly dosing produces consistent, sustained effects throughout the dosing interval. Semaglutide’s long half-life (~7 days) maintains therapeutic drug levels with weekly administration.
Practical Application
While this Phase 2 trial predates current clinical practice, its findings directly shaped how semaglutide is used today. The dose escalation principle established here underlies current prescribing: start low (0.25 mg weekly), increase gradually (every 4 weeks), and titrate to effect while monitoring tolerability.
The dose-response relationship means patients with suboptimal response at lower doses can expect additional benefit from dose increases. The ultimately approved doses (0.5 mg, 1.0 mg, 2.0 mg for diabetes; 2.4 mg for obesity) were selected based on this and subsequent Phase 2 work.
When patients experience GI side effects during semaglutide initiation, this study supports the value of slower titration. Extending time at lower doses before escalation often improves tolerability while still achieving therapeutic effect.
Broader Evidence Context
This Phase 2 trial launched the comprehensive semaglutide development program. The SUSTAIN Phase 3 trials (SUSTAIN 1-10) confirmed and extended these findings across diverse populations and comparators. SUSTAIN-6 demonstrated cardiovascular safety and benefit. The Phase 2 dose-finding for obesity (O’Neil 2018) established the 2.4 mg weekly dose for the STEP program.
The superiority over liraglutide observed here has been consistently replicated in subsequent trials (SUSTAIN 10 for diabetes; Phase 2 obesity trial), establishing semaglutide as the most potent GLP-1 RA prior to the emergence of dual agonists.
Study Limitations
The 12-week duration is short for chronic disease management. The dose range (up to 1.6 mg) differs from ultimately approved doses. The liraglutide comparison was open-label, potentially biasing subjective outcomes. Long-term cardiovascular and safety outcomes weren’t assessed.
Bottom Line
This Phase 2 dose-finding study established semaglutide’s dose-dependent efficacy for glycemic control and weight loss, demonstrated superiority over liraglutide, and identified the importance of gradual dose escalation for GI tolerability. These foundational findings informed the development program that led to semaglutide becoming the most widely used GLP-1 RA.
Source: Nauck MA, et al. “A Phase 2 Randomized Dose-Finding Study of the Novel Once-Weekly Human GLP-1 Analog Semaglutide Compared With Placebo and Open-Label Liraglutide in Patients With Type 2 Diabetes.” Diabetes Care, 2016;39(2):231-241. Read article
