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 NameActive ComparatorsBackground RegimenTime Point for Primary Efficacy Analysis, weeksRelative 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 dailyMetformin ± SGLT2  inhibitor26Similar (–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 dailyMetformin26Significantly 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 dailyMetformin, SU, or  both26Significantly 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 dailyMetformin24Similar 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 dailyMetformin, SU, or  SGLT2 inhibitor, or any combination thereof30Significantly 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 dailyMetformin26Similar (–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 dailyMetformin +  pioglitazone26Significantly 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 dailyMetformin and/or  SU, or metformin ± pioglitazone26Significantly 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 dailyMetformin, SU, and  TZD, alone or in combination24Significantly 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 dailyMetformin, SU, TZD,  or a combination of two30Significantly 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 weekly1–2 OADs  (metformin, SU, TZD)56Significantly 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 weeklyMetformin40Significantly 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.