Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA
Authors' conclusion
In people with type 2 diabetes, retatrutide showed clinically meaningful improvements in glycaemic control and robust reductions in bodyweight, with a safety profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists. These phase 2 data also informed dose selection for the phase 3 programme.
Study context
- Population
- Adults aged 18–75 years with T2D, HbA1c 7.0–10.5% and BMI 25–50 kg/m², on diet and exercise alone or stable metformin275 in efficacy analyses
- Participants
- 281 adults
- Comparison
- Once-weekly retatrutide vs placebo vs dulaglutide 1.5 mg
- Placebon = 45reference
- Dulaglutide 1.5 mgn = 46reference
- Retatrutide 0.5 mgn = 47
- 4 mg escalationn = 23
- 4 mgn = 24
- 8 mg slow escalationn = 26
- 8 mg fast escalationn = 24
- 12 mg escalationn = 46
- Primary endpoint
- Change in HbA1c from baseline
- Follow-up
- 24 weeks
Methodological detailsdouble-blind, double-dummy, placebo-controlled, active comparator-controlled, parallel-group, phase 2, 42 centres in the USA, 237 (84%) completed the study; 222 (79%) completed study treatment
- Double-blind
- Double-dummy
- Placebo-controlled
- Active comparator-controlled
- Parallel-group
- Phase 2
- 42 centres in the USA
- 237 (84%) completed the study; 222 (79%) completed study treatment
Primary result
As reported in the abstract
Retatrutide 0.5 mg
−0.43
least-squares mean · SE 0.20 · %
4 mg escalation
−1.39
least-squares mean · SE 0.14 · %
4 mg
−1.30
least-squares mean · SE 0.22 · %
8 mg slow escalation
−1.99
least-squares mean · SE 0.15 · %
8 mg fast escalation
−1.88
least-squares mean · SE 0.21 · %
12 mg escalation
−2.02
least-squares mean · SE 0.11 · %
Placebo
−0.01
least-squares mean · SE 0.21 · %
Dulaglutide 1.5 mg
−1.41
least-squares mean · SE 0.12 · %
8 mg slow escalation vs Dulaglutide 1.5 mg: P = 0.0019 · 12 mg escalation vs Dulaglutide 1.5 mg: P = 0.0002
- HbA1c reductions with retatrutide significantly greater than placebo in all but the 0.5 mg group
- P < 0.0001
Secondary outcomes
| Outcome | Values | P value |
|---|---|---|
| Bodyweight decrease · 36 weeks4 mg escalation vs Placebo · greater weight decrease with retatrutide | Retatrutide 0.5 mg 3.19 (SE 0.61) % · 4 mg escalation 7.92 (SE 1.28) % · 4 mg 10.37 (SE 1.56) % · 8 mg slow escalation 16.81 (SE 1.59) % · 8 mg fast escalation 16.34 (SE 1.65) % · 12 mg escalation 16.94 (SE 1.30) % · Placebo 3.00 (SE 0.86) % · Dulaglutide 1.5 mg 2.02 (SE 0.72) % | P = 0.0017 |
- Bodyweight decrease — Weight decrease significantly greater than placebo for other retatrutide doses ≥4 mg
- p<0.0001
- Bodyweight decrease — Weight decrease significantly greater than dulaglutide 1.5 mg for retatrutide doses ≥4 mg
- all p<0.0001
HbA1c change · 36 weeks
- Findings consistent at 36 weeks
Severe hypoglycaemia and deaths
- Severe hypoglycaemia
- 0
- Deaths
- 0
Safety
Mild-to-moderate gastrointestinal adverse events
- Mild-to-moderate gastrointestinal adverse events — All retatrutide groups combined
- 67 (35%) of 190
- Mild-to-moderate gastrointestinal adverse events: range across retatrutide groups from 0.5 mg to 8 mg fast escalation
Original publication
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