Introduction

Obesity affects 650 million adults globally, driving morbidity, mortality, and economic burden through complications like cardiovascular disease and diabetes. Lifestyle interventions alone often fail due to physiological mechanisms that hinder weight loss maintenance, confirming obesity as a complex metabolic disorder. Clinical guidelines now recommend anti-obesity medications. GLP-1 receptor agonists have shown efficacy, and combining GIP and GLP-1 agonism may enhance results. Tirzepatide, a dual GIP/GLP-1 receptor agonist approved for type 2 diabetes, demonstrated synergistic effects and significant weight reduction in preclinical and phase 2 studies, supporting its potential as an effective obesity treatment.

Aim

To assess the efficacy and safety of tirzepatide in obese and overweight adults who did not have diabetes.

Method

Study Design

Patient Inclusion Criteria

Treatment Strategy

• Participants were assigned in 1:1:1:1 ratio to receive subcutaneous administration of tirzepatide at a dose of 5 mg, 10 mg, 15 mg or placebo once weekly for 72 weeks after a screening period of 2 weeks
• This included a dose escalation period upto 20 weeks
• Tirzepatide (or matching placebo) was started at 2.5 mg once weekly and increased by 2.5 mg every 4 weeks during dose escalation, reaching a maintenance dose of up to 15 mg weekly by week 20
• After 72 weeks, participants without prediabetes entered a 4-week safety follow-up, while those with prediabetes continued their assigned treatment for an additional 2-year trial period

Endpoints

Primary Endpoint

• % Change in the body weight at week 72 from baseline
• Weight reduction of 5% or more at week 72 

Secondary Endpoints

• Weight reduction of 10% or more, 15% or more, and 20% or more at week 72
• Change in weight from baseline to week 20
• Change from baseline to week 72 in waist circumference
• Change from baseline to week 72 in Systolic blood pressure
• Change from baseline to week 72 in Fasting insulin and lipid levels
• Change from baseline to week 72 in The physical function score on the 36-Item Short Form Health Survey (SF-36)
• Total body-fat mass from baseline to week 72 was assessed in a subgroup

Safety Endpoint

Results

• The trial included 2539 participants, of which 86% completed the study
• The baseline demographics and clinical characteristics were similar across all the groups
• Baseline characteristics of cohort were as follows
  1. Mean body weight - 104.8 kg
  2. Mean BMI - 38.0 kg/m²
  3. Mean waist circumference - 114.1 cm
  4. 94.5% of participants had a BMI of 30 or higher
  5. average duration of obesity – 14.4 years
  6. 40.6% had pre-diabetes 
• Tirzepatide was superior to placebo with respect to weight reduction at week 72 with estimated treatment differences relative to placebo of -13.5 percentage points for the 5-mg dose, -18.9 percentage points for the 10-mg dose, and -20.1 percentage points for the 15-mg dose (p<0.001 for all comparisons) as seen in Table 1.
• The percentage of participants who had weight reduction of 5% or more was higher in the tirzepatide groups as seen in Table 1; p<0.001 for all comparisons with placebo

Table 1. Changes in primary endpoints

	Tirzepatide 5 mg	Tirzepatide 10 mg	Tirzepatide 15 mg	Placebo
Mean change in weight at week 72	-16%	-21.4%	-22.5%	-2.4%
Body weight reduction of 5% or more at week 72	89%	96%	96%	28%

• Tirzepatide resulted in improvements in blood pressure, fasting insulin and lipid levels
• At 72 weeks, Among the participants with prediabetes at baseline, 95.3% reverted to normoglycemia vs 61.9% in placebo group
• The incidence of at least one AE is seen in Figure 1.

Figure 1. Incidence of atleast 1 adverse event

Figure 2. Incidence of serious AEs

• The most common AEs events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation.
• Treatment discontinuation due to AEs occurred in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively.

Conclusion

N Engl J Med. 2022;387(3):205-216.