A large-scale real-world study has demonstrated that tirzepatide provides significantly greater weight reduction than semaglutide in adults with overweight or obesity, with consistent benefits observed across various patient populations.
The research, conducted using Truveta Data from a collective of US healthcare systems, analyzed outcomes from 41,223 patients who initiated either tirzepatide (9,193 patients) or semaglutide (32,030 patients) between May 2022 and September 2023.
Superior Weight Loss Outcomes with Tirzepatide
After propensity score matching to balance baseline characteristics, researchers found that tirzepatide users were substantially more likely to achieve clinically meaningful weight loss milestones compared to those taking semaglutide.
Within one year of treatment, 81.8% of tirzepatide users achieved ≥5% weight loss versus 64.6% of semaglutide users. More impressive differences emerged at higher thresholds, with 62.1% of tirzepatide patients reaching ≥10% weight loss (compared to 38.0% with semaglutide) and 42.3% achieving ≥15% weight loss (versus just 19.3% with semaglutide).
"The hazard ratios comparing tirzepatide to semaglutide were 1.76 for 5% weight loss, 2.42 for 10% weight loss, and 3.04 for 15% weight loss, indicating substantially higher likelihood of achieving these clinically important thresholds with tirzepatide," the researchers noted.
Percentage Weight Reduction Over Time
The study also examined mean percentage changes in body weight at specific time points:
- At 3 months: -5.9% with tirzepatide vs. -3.6% with semaglutide
- At 6 months: -10.1% with tirzepatide vs. -5.9% with semaglutide
- At 12 months: -15.2% with tirzepatide vs. -7.9% with semaglutide
After adjusting for residual confounding factors, the absolute difference in weight loss between tirzepatide and semaglutide was -2.3% at 3 months, -4.3% at 6 months, and -7.2% at 12 months.
Consistent Benefits Across Patient Subgroups
The superior efficacy of tirzepatide remained consistent across different analytical approaches and patient populations. Notably, the benefits were observed in both patients with and without type 2 diabetes (T2D), though those without T2D experienced larger weight reductions overall with both medications.
"Treatment effects were consistent in direction and significance between methodological approaches and within the subgroup of patients with T2D," the researchers stated.
Safety Profile Comparison
An important finding was the comparable safety profile between the two medications. No significant differences were observed in the risk of gastrointestinal adverse events, which are commonly associated with GLP-1 receptor agonists.
Gastroenteritis was the most common adverse event, occurring at rates of 21.0 and 19.1 cases per 1,000 person-years for tirzepatide and semaglutide, respectively. Other monitored adverse events included bowel obstruction, cholecystitis, cholelithiasis, gastroparesis, and pancreatitis.
Study Strengths and Limitations
The research represents the first real-world comparative effectiveness study of tirzepatide and semaglutide in adults with overweight or obesity. Its strengths include the large sample size, inclusion of patients who might be excluded from clinical trials (such as those with major depressive disorder), and the use of multiple analytical approaches to confirm findings.
However, the researchers acknowledged several limitations. Weight loss is directly observable to patients, which may result in informative censoring—patients seeing desired results might be more likely to continue treatment. Additionally, medication shortages during the study period may have affected discontinuation rates.
"While a modified intention-to-treat analysis inclusive of post-discontinuation weights showed smaller reductions in weight, differences between tirzepatide and semaglutide were similar," the researchers noted.
Clinical Implications
These findings align with existing evidence from randomized controlled trials (RCTs) while extending knowledge to real-world populations. The results suggest that tirzepatide may be a more effective option for weight management in clinical practice for patients with overweight or obesity, regardless of diabetes status.
The researchers emphasized that future work is needed to compare the effects of tirzepatide and semaglutide on other key endpoints, particularly cardiovascular outcomes. Additionally, they noted that studies comparing the higher-dose formulations specifically labeled for weight loss (rather than diabetes) would be valuable.
A head-to-head clinical trial comparing tirzepatide to semaglutide in patients with overweight or obesity without T2D (SURMOUNT-5) is currently underway, with results expected in late 2024, which will provide further evidence on the comparative efficacy of these medications.
