Findings

What does this study add?

Weight change from baseline ranged from 16.0% to 22.5% with tirzepatide (5–15 mg) versus 2.4% with placebo (efficacy estimand).
Effects were seen very early, with a response as soon as 4 weeks.
Over 90% of patients achieved the prespecified goal of ≥5% weight loss, half achieved ≥20%, and over one-third lost more than 25% of their initial body weight.
At an individual level, 97.7% lost weight with tirzepatide, with heterogeneity seen in response.
All prespecified cardiometabolic measures improved with tirzepatide, including waist circumference, body composition, HbA1c, fasting glucose and insulin, and blood pressure.
The reduction in waist circumference was 5-times greater with tirzepatide than placebo – up to 19.9 cm compared to 3.4 cm with placebo.
The reduction in total fat mass – as measured by DXA – was ~4-times greater with tirzepatide, with a reduction of 33.9% with tirzepatide versus 8.2% with placebo.
Baseline HbA1c decreased by 0.5%, and of those who had prediabetes over 95.3% reverted to normoglycemia with tirzepatide, compared to 61.9% in the placebo group.
Overall, there was a 47% decrease in fasting insulin, with a change from baseline of 4.94–5.82 mIU/L, compared to a reduction of 1.14 with placebo.
In terms of safety, similar proportions reported adverse events, but there was an increase in the incidence of death on tirzepatide compared to placebo.
Gastrointestinal adverse events were the most common – with one-third of patients experiencing nausea at some point; however, this was usually mild and transitory, and decreased over time.
There were 4 positively adjudicated cases of pancreatitis evenly distributed across treatment groups.
Cholecystitis was reported more frequently in the tirzepatide groups compared to placebo.
Small, transient increases in pulse rate were observed with all doses of tirzepatide.
Overall, the tolerability and safety profile of tirzepatide was consistent with other injectable, incretin-based therapies for obesity.