Procedures during the double-blind treatment period
gastrointestinal symptoms
Tirzepatide and matched placebo were administered once weekly as a subcutaneous injection using a single-dose pen. The starting dose of tirzepatide was 2.5 mg, increasing by 2.5 mg every 4 weeks until an MTD dose of 10 or 15 mg was reached. To optimize tolerability and adherence, gastrointestinal symptoms could be managed by dietary counseling, symptomatic medications according to the investigator’s discretion or skipping of a single dose of treatment. During the first 24 weeks of the treatment period, if these mitigations were not successful one cycle of tirzepatide dose de- and re-escalation (in 2.5 mg increments) was allowed for participants unable to tolerate any dose between 7.5 and 15 mg inclusive; participants unable to tolerate 2.5 or 5 mg were discontinued from study drug but remained in the study for continued follow-up. Participants who did not tolerate up to 10 mg even after one de- and re-escalation attempt were discontinued from study drug but remained in the study for continued follow-up. Dose adjustments were not permitted after the first 24 weeks of treatment.Throughout the postrandomization period, participants continued to consult with a dietitian or other qualified healthcare professional. Lifestyle counseling sessions occurred every 12 weeks and focused on consumption of a healthy balanced diet, with a 500 kcal per day deficit and continuation of physical activity. Use of the diet and exercise log was encouraged. In between counseling sessions, diet and exercise goals were reinforced by site staff at every monthly visit.Participants were permitted to use concomitant medications that they required during the study, except for certain agents specified in the protocol that could interfere with the assessment of efficacy and safety characteristics of the study treatments.