Tirzepatide once weekly for the treatment of obesity offers a groundbreaking solution with significant weight loss results. In clinical trials, participants experienced a significant reduction in body weight of up to 20.9%.This dual GIP and GLP-1 receptor agonist is emerging as a highly effective option for obesity treatment, improving both weight management and metabolic health with an acceptable safety profile.
Abstract
Background
Obesity is a major global health issue, contributing significantly to mortality and morbidity. The novel medication tirzepatide, which combines glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists, has shown promise, but its effectiveness and safety profile in treating obesity are not yet fully established.
Phase 3 Study of Tirzepatide for Obesity Management
This Phase 3, double-blind, randomized, controlled trial explored the effects of tirzepatide on obesity over a period of 72 weeks. The study enrolled 2,539 adults with a body mass index (BMI) of 30 or higher, or 27 or higher with at least one weight-related condition (excluding diabetes). Participants were randomly assigned to receive tirzepatide via weekly subcutaneous injections at doses of 5 mg, 10 mg, or 15 mg, or a placebo. The study featured a 20-week dose-escalation phase. Key outcomes included the percentage change in body weight from baseline and the achievement of a weight loss of 5% or greater. The treatment-regimen estimand approach was applied to assess the effects of the intervention, irrespective of whether participants discontinued treatment.
Results
Baseline characteristics showed a mean body weight of 104.8 kg and an average BMI of 38.0, with 94.5% of participants having a BMI of 30 or more. By week 72, participants on tirzepatide achieved substantial weight loss:
- 5 mg dose: −15.0% (95% CI, −15.9 to −14.2)
- 10 mg dose: −19.5% (95% CI, −20.4 to −18.5)
- 15 mg dose: −20.9% (95% CI, −21.8 to −19.9)
In contrast, the placebo group had a weight reduction of −3.1% (95% CI, −4.3 to −1.9), with all tirzepatide comparisons being statistically significant (P<0.001). The percentage of participants achieving a weight reduction of 5% or more was:
- 5 mg dose: 85% (95% CI, 82 to 89)
- 10 mg dose: 89% (95% CI, 86 to 92)
- 15 mg dose: 91% (95% CI, 88 to 94)
This compares to 35% (95% CI, 30 to 39) in the placebo group. Additionally:
- 10 mg dose: 50% (95% CI, 46 to 54)
- 15 mg dose: 57% (95% CI, 53 to 61)
achieved a weight reduction of 20% or more, versus only 3% (95% CI, 1 to 5) in the placebo group (P<0.001 for all comparisons). Improvements were observed in all pre-specified cardiometabolic parameters with tirzepatide. Common adverse events were gastrointestinal, generally mild to moderate, and mainly occurred during dose escalation. Treatment discontinuation due to adverse events was 4.3%, 7.1%, and 6.2% in the 5-mg, 10-mg, and 15-mg tirzepatide groups, respectively, compared to 2.6% in the placebo group.
Once-Weekly Tirzepatide for Obesity
Overview
Obesity is the most common chronic disease globally, affecting around 650 million adults. Its associated complications, such as cardiovascular diseases and type 2 diabetes, significantly contribute to global morbidity and mortality, as well as economic strain. Effective treatments that lead to significant weight loss can enhance outcomes for individuals dealing with obesity.
Historically, obesity management has relied heavily on lifestyle changes like diet and exercise. However, these methods often encounter physiological resistance that hampers substantial and sustained weight loss, highlighting obesity as a complex metabolic disorder involving both central and peripheral mechanisms. This complexity has led clinical guidelines to increasingly recommend anti-obesity medications for those with obesity or those who are overweight and have weight-related health issues. Recent research indicates that long-acting glucagon-like peptide-1 (GLP-1) receptor agonists offer substantial efficacy with an acceptable safety profile by targeting endogenous nutrient-stimulated hormone pathways. Additionally, glucose-dependent insulinotropic polypeptide (GIP), another hormone involved in energy regulation, works through receptor signaling in the brain and adipose tissue. A compound that simultaneously targets both GIP and GLP-1 receptors could potentially offer enhanced efficacy in weight reduction.
Tirzepatide is a once-weekly subcutaneous injectable peptide, approved by the FDA for type 2 diabetes, that acts on both GIP and GLP-1 receptors. It was engineered from the native GIP sequence and exhibits agonist activity at both receptors. Preclinical studies showed that tirzepatide binds to GIP receptors with an affinity comparable to native GIP, while its affinity for GLP-1 receptors is approximately five times lower than that of native GLP-1. This dual receptor activation may provide superior weight reduction compared to GLP-1 receptor activation alone. Phase 2 studies in individuals with type 2 diabetes demonstrated clinically significant weight loss, leading to further exploration of tirzepatide for obesity treatment. The SURMOUNT-1 trial was designed to assess tirzepatide’s efficacy and safety in adults with obesity or overweight without diabetes.
Methods
Trial Design
The SURMOUNT-1 trial was a phase 3, multicenter, double-blind, randomized, placebo-controlled study conducted across 119 sites in nine countries. The trial adhered to the Declaration of Helsinki and Good Clinical Practice guidelines and received approval from an independent ethics committee or institutional review board at each site. All participants provided written informed consent. Sponsored by Eli Lilly, the trial was designed and managed by the sponsor, while trial site investigators handled data collection. The sponsor was responsible for site monitoring, data aggregation, and analysis. All authors participated in data interpretation and manuscript review, with full access to trial data and adherence to protocol.
Participants
Eligible participants were adults aged 18 or older with a body mass index (BMI) of 30 or higher, or a BMI of 27 or higher with at least one weight-related health condition (e.g., hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease), who had attempted and failed dietary weight loss efforts. Key exclusion criteria included diabetes, significant weight changes (>5 kg) in the 90 days prior to screening, prior or planned obesity surgery, and use of weight loss medications within the previous 90 days. Detailed eligibility criteria are provided in the Supplementary Appendix.
Procedures
Following a 2-week screening period, participants were randomly assigned in a 1:1:1:1 ratio to receive tirzepatide at doses of 5 mg, 10 mg, or 15 mg, or a placebo, administered subcutaneously once a week for a total of 72 weeks, alongside a lifestyle intervention. The lifestyle intervention included consistent counseling sessions conducted by a dietitian or certified healthcare provider. The focus was on adhering to a balanced diet with a daily caloric deficit of 500 calories and engaging in a minimum of 150 minutes of physical activity each week.
Randomization was performed with stratification based on country, gender, and the presence of prediabetes, following the guidelines set forth by the American Diabetes Association in 2019. Participants underwent a structured 72-week treatment phase that included up to 20 weeks of dose escalation. Tirzepatide treatment began at 2.5 mg weekly (or matching placebo) and was incrementally increased by 2.5 mg every 4 weeks during the dose-escalation phase to reach a maximum of 15 mg weekly by week 20. After the 72-week treatment phase, participants without prediabetes at randomization underwent a 4-week safety follow-up. Participants with prediabetes continued their assigned treatment for an additional 2 years. This report details the outcomes of the 72-week treatment phase and the subsequent 4-week safety follow-up.
End Points and Assessments
The primary endpoints were the percentage change in body weight from baseline to week 72 and achieving a weight reduction of 5% or more at week 72. Key secondary endpoints included weight reductions of 10%, 15%, and 20% or more at week 72, changes in weight from baseline to week 20, changes in waist circumference, systolic blood pressure, fasting insulin levels, lipid profiles, and the physical function score on the 36-Item Short Form Health Survey (SF-36). Additionally, total body fat mass change from baseline to week 72 was assessed in a subgroup of 255 participants using dual-energy X-ray absorptiometry.
Safety evaluations included recording adverse and serious adverse events during the trial. Laboratory assessments followed the trial protocol.
Statistical Analysis
A sample size of 2400 participants was calculated to ensure over 90% power to demonstrate the superiority of tirzepatide (at 10 mg, 15 mg, or both) compared to placebo for the primary endpoints, with a two-sided significance level of 0.025. This calculation assumed an 11-percentage-point difference in mean percentage weight reduction from baseline at 72 weeks between tirzepatide and placebo, a common standard deviation of 10%, and a 25% dropout rate.
Both efficacy and safety endpoints were analyzed using data from all randomly assigned participants (intention-to-treat population). Two estimands were employed to assess treatment efficacy from different perspectives and to account for various intercurrent events: the “treatment regimen” estimand, which reflects the average treatment effect of tirzepatide versus placebo for all randomized participants, regardless of treatment discontinuation, and the “efficacy” estimand, which represents the average treatment effect if treatment was administered as intended.
Details regarding estimands, handling of missing values, and statistical analysis methods are included in the Supplementary Appendix. Results are reported based on the treatment-regimen estimand unless specified otherwise. The type I error rate was managed separately for each estimand when assessing primary and key secondary endpoints, utilizing a graphical method to ensure control.
Results
Participants
The trial, conducted from December 2019 to April 2022, enrolled 2539 participants. Overall, 86.0% completed the primary trial treatment period, with completion rates of 88.4% to 89.8% in the tirzepatide groups and 77.0% in the placebo group. Adherence to treatment was 81.9%, with 83.5% to 85.7% across the tirzepatide groups and 73.6% in the placebo group. Discontinuations due to adverse events were 4.3%, 7.1%, and 6.2% for the 5 mg, 10 mg, and 15 mg tirzepatide groups, respectively, and 2.6% for the placebo group.
Demographic and Clinical Characteristics
The participants had an average age of 44.9 years, with a majority being female (67.5%) and White (70.6%). Their mean body weight was 104.8 kg, average BMI was 38.0, and mean waist circumference was 114.1 cm. A significant proportion (94.5%) had a BMI of 30 or above. The average duration of obesity was 14.4 years, with 40.6% having prediabetes at the start, and nearly two-thirds experiencing one or more weight-related health issues.
Change in Body Weight
For the treatment-regimen estimand, the average weight loss at week 72 was as follows:
- 5 mg tirzepatide: −15.0% (95% CI, −15.9 to −14.2)
- 10 mg tirzepatide: −19.5% (95% CI, −20.4 to −18.5)
- 15 mg tirzepatide: −20.9% (95% CI, −21.8 to −19.9)
- Placebo: −3.1% (95% CI, −4.3 to −1.9)
All tirzepatide doses resulted in significantly greater weight loss than the placebo. The estimated differences in treatment effects were −11.9 percentage points (95% CI, −13.4 to −10.4) for the 5 mg dose, −16.4 percentage points (95% CI, −17.9 to −14.8) for the 10 mg dose, and −17.8 percentage points (95% CI, −19.3 to −16.3) for the 15 mg dose, with all comparisons being statistically significant (P<0.001).
For the efficacy estimand, the mean weight changes at week 72 were:
- 5 mg tirzepatide: −16.0% (95% CI, −16.8 to −15.2), 16.1 kg (35.5 lb)
- 10 mg tirzepatide: −21.4% (95% CI, −22.2 to −20.6), 22.2 kg (48.9 lb)
- 15 mg tirzepatide: −22.5% (95% CI, −23.3 to −21.7), 23.6 kg (52.0 lb)
- Placebo: −2.4% (95% CI, −3.2 to −1.6), 2.4 kg (5.3 lb)
Treatment with tirzepatide resulted in more participants achieving weight reductions of 10% or more, 15% or more, and 20% or more compared to placebo, with statistical significance (P<0.001). For the exploratory endpoint of a 25% or more weight reduction, 15% (95% CI, 12 to 18), 32% (95% CI, 29 to 36), and 36% (95% CI, 32 to 40) of participants in the 5 mg, 10 mg, and 15 mg groups, respectively, met this target, compared to 1.5% (95% CI, 0 to 3) in the placebo group.
Cardiometabolic Risk Factors and Physical Function
Tirzepatide led to significant improvements in waist circumference, blood pressure (systolic and diastolic), fasting insulin levels, and lipid profiles compared to placebo. Most participants with prediabetes in the tirzepatide groups reverted to normoglycemia by week 72, compared to 61.9% in the placebo group. Improvements in SF-36 physical function scores were also observed with tirzepatide.
Change in Body Composition
Participants treated with tirzepatide experienced a mean reduction in total body fat mass of 33.9%, compared to 8.2% with placebo, resulting in an estimated treatment difference of −25.7 percentage points (95% CI, −31.4 to −20.0). The ratio of fat mass to lean mass decreased more with tirzepatide than with placebo.
Safety
Adverse events were reported by 78.9% to 81.8% of tirzepatide-treated participants, compared to 72.0% in the placebo group. Gastrointestinal issues (nausea, diarrhea, constipation) were the most common adverse events and were more frequent in the tirzepatide groups but were mostly mild to moderate and transient. Serious adverse events occurred in 6.3% of participants, with no significant differences between tirzepatide and placebo groups. There were four cases of adjudicated pancreatitis, evenly distributed across all groups, including placebo, and no cases of medullary thyroid cancer. Cholecystitis was more frequent with tirzepatide but occurred in a low percentage of participants.
Discussion
This trial demonstrated substantial and sustained weight reduction with tirzepatide, with average reductions of 19.5% and 20.9% for the 10 mg and 15 mg doses, respectively, compared to 3.1% with placebo. These results are notably higher compared to other antiobesity medications. The efficacy of tirzepatide may be attributed to its dual action on GIP and GLP-1 receptors, targeting multiple pathways involved in energy homeostasis.
A reduction of 5% or more in body weight is considered clinically meaningful, and the majority of participants in the 10 mg and 15 mg groups achieved this, along with significant reductions in higher weight-loss targets. Tirzepatide’s efficacy was superior to older antiobesity medications and showed comparable or greater efficacy than recent therapies like semaglutide.
Improvements in cardiovascular and metabolic risk factors were observed with tirzepatide, including significant fat mass reduction and better body composition. Nearly all participants with prediabetes reverted to normoglycemia, suggesting potential long-term benefits in reducing the risk of cardiovascular diseases and type 2 diabetes.
Safety was consistent with previous findings and similar to other incretin-based therapies. Although gastrointestinal events were more frequent, they were generally mild. Cholecystitis occurred more often with tirzepatide but was infrequent overall.
Overall, the trial’s strengths include its global scope, large sample size, and high completion rate, despite the Covid-19 pandemic. Future research is needed to explore the long-term effects and benefits of tirzepatide, particularly in diverse populations and in comparison with other obesity treatments.
