TABLE 2.
Summary of Safety and Efficacy Results From Global Phase 3 Head-to-Head Studies of GLP-1 Receptor Agonists Approved for Use in the United States*
| Trial Name | Active Comparators | Background Regimen | Time Point for Primary Efficacy Analysis, weeks | Relative A1C Reduction, % (ETD [95% CI], P) | Relative Weight Loss, kg (ETD [95% CI], P) | Safety and Tolerability Observations† |
|---|---|---|---|---|---|---|
| Once daily vs. once/twice daily | ||||||
| PIONEER 4 (64) | Oral semaglutide 14 mg once daily vs. liraglutide 1.8 mg once daily | Metformin ± SGLT2 inhibitor | 26 | Similar (–0.1 [−0.3 to 0.0], <0.0001 for noninferiority‡) | Significantly greater with oral semaglutide than liraglutide (−1.2 [−1.9 to −0.6], 0.0003‡) | Nausea: 20 vs. 18% |
| Diarrhea: 15 vs. 11% | ||||||
| Vomiting: 9 vs. 5% | ||||||
| LIRA-LIXI (65) | Liraglutide 1.8 mg once daily vs. lixisenatide 20 µg once daily | Metformin | 26 | Significantly greater with liraglutide than lixisenatide (–0.6 [–0.8 to –0.4], <0.0001) | Similar (–0.6 kg [–1.6 to 0.4], 0.23) | Nausea: 22 vs. 22% |
| Diarrhea: 12 vs. 10% | ||||||
| Vomiting: 7 vs. 9% | ||||||
| LEAD-6 (66) | Liraglutide 1.8 mg once daily vs. exenatide 10 µg twice daily | Metformin, SU, or both | 26 | Significantly greater with liraglutide than exenatide (–0.33 [–0.47 to –0.18], <0.0001) | Similar (–0.38 [–0.99 to 0.23], 0.2235) | Nausea: 26 vs. 28% |
| Diarrhea: 12 vs. 12% | ||||||
| Vomiting: 6 vs. 10% | ||||||
| GetGoal-X (67) | Lixisenatide 20 µg once daily vs. exenatide 10 µg twice daily | Metformin | 24 | Similar based on noninferiority margin of 0.4% for upper CI (0.17 [0.03–0.30], N/R) | Significantly less with lixisenatide than exenatide (1.02 [0.46–1.58], N/R) | Nausea: 25 vs. 35% |
| Diarrhea: 10 vs. 13% | ||||||
| Vomiting: 10 vs. 13% | ||||||
| Once weekly vs. once/twice daily | ||||||
| SUSTAIN-10 (34) | Subcutaneous semaglutide 1.0 mg once weekly vs. liraglutide 1.2 mg once daily | Metformin, SU, or SGLT2 inhibitor, or any combination thereof | 30 | Significantly greater with semaglutide than liraglutide (–0.69 [–0.82 to –0.56], <0.0001) | Significantly greater with semaglutide than liraglutide (–3.83 [–4.57 to –3.09], <0.0001) | Nausea: 22 vs. 16% |
| Diarrhea: 16 vs. 12% | ||||||
| Vomiting: 10 vs. 8% | ||||||
| AWARD-6 (37) | Dulaglutide 1.5 mg once weekly vs. liraglutide 1.8 mg once daily | Metformin | 26 | Similar (–0.06 [–0.19 to 0.07], <0.0001 for noninferiority) | Significantly less with dulaglutide than liraglutide (0.71 [0.17–1.26], 0.011) | Nausea: 20 vs. 18% |
| Diarrhea: 12 vs. 12% | ||||||
| Vomiting: 7 vs. 8% | ||||||
| AWARD-1 (68) | Dulaglutide 0.75/ 1.5 mg once weekly vs. exenatide 10 µg twice daily | Metformin + pioglitazone | 26 | Significantly greater with dulaglutide than exenatide (1.5 mg: –0.52 [–0.66 to –0.39], <0.001; 0.75 mg: –0.31 [–0.44 to –0.18], <0.001) | Similar for dulaglutide 1.5 mg and exenatide (–0.24 [N/R], 0.474) | Nausea: 29/17%(1.5 mg/0.75 mg) vs. 28% |
| Significantly less with dulaglutide 0.75 mg than exenatide (1.27 [N/R], <0.001) | Diarrhea: 13/9% vs. 8% | |||||
| Vomiting: 17/6% vs. 12% | ||||||
| DURATION-6 (38) | Exenatide 2 mg once weekly vs. liraglutide 1.8 mg once daily | Metformin and/or SU, or metformin ± pioglitazone | 26 | Significantly less with exenatide than liraglutide (0.21 [0.08–0.33], 0.0018) | Significantly less with exenatide than liraglutide (0.90 [0.39–1.40, 0.0005) | Nausea: 9 vs. 21% |
| Diarrhea: 6 vs. 13% | ||||||
| Vomiting: 4 vs. 11% | ||||||
| DURATION-5 (69) | Exenatide 2 mg once weekly vs. exenatide 10 µg twice daily | Metformin, SU, and TZD, alone or in combination | 24 | Significantly greater with exenatide once weekly than exenatide twice daily (–0.7 [–0.9 to –0.4], <0.0001) | Similar (–0.95 [–1.9 to 0.01], <0.05) | Nausea: 14 vs. 35% |
| Diarrhea: 9 vs. 4% | ||||||
| Vomiting: 5 vs. 9% | ||||||
| DURATION-1 (70) | Exenatide 2 mg once weekly vs. exenatide 10 µg twice daily | Metformin, SU, TZD, or a combination of two | 30 | Significantly greater with exenatide once weekly than exenatide twice daily (–0.33 [–0.54 to –0.12], 0.0023) | Similar (N/R [–1.3 to 1.1], 0.89) | Nausea: 26 vs. 34% |
| Diarrhea: 14 vs. 13% | ||||||
| Vomiting: 11 vs. 19% | ||||||
| Once weekly vs. once weekly | ||||||
| SUSTAIN-3 (35) | Subcutaneous semaglutide 1 mg once weekly vs. exenatide 2 mg once weekly | 1–2 OADs (metformin, SU, TZD) | 56 | Significantly greater with semaglutide than exenatide (–0.62 [–0.80 to –0.44], <0.0001) | Significantly greater with semaglutide than exenatide (–3.78 [–4.58 to –2.98], <0.0001) | Nausea: 22 vs. 12% |
| Diarrhea: 11 vs. 8% | ||||||
| Vomiting: 7 vs. 6% | ||||||
| SUSTAIN-7 (36) | Subcutaneous semaglutide 0.5/1 mg once weekly vs. dulaglutide 0.75/1.5 mg once weekly | Metformin | 40 | Significantly greater with semaglutide than dulaglutide (0.5 vs. 0.75 mg: –0.40 [–0.55 to –0.25]; 1 vs. 1.5 mg: –0.41 [–0.57 to –0.25]; < 0.0001 for both) | Significantly greater with semaglutide than dulaglutide (0.5 vs. 0.75 mg: –2.26 [–3.02 to –1.51]; 1 vs. 1.5 mg: –3.55 [–4.32 to –2.78], <0.0001 for both) | Nausea: 23/21 (0.5/1.0 mg) vs. 13/20% (0.75/1.5 mg) |
| Diarrhea: 14/14 vs. 8/18% | ||||||
| Vomiting: 10/10 vs. 4/10% | ||||||
*
The HARMONY 7 trial of albiglutide versus liraglutide (71) has been omitted because albiglutide is no longer available commercially in the United States. †Percentages are proportions of patients reporting the events described.
‡
Treatment policy estimand (regardless of trial product discontinuation or rescue medication use in all randomized patients). AE, adverse event; ETD, estimated treatment difference; N/R, not reported; OAD, oral antidiabetic drug; SU, sulfonylurea; TZD, thiazolidinedione.