Zepbound vs Wegovy: New Trial Data and the Launch of the KwikPen Device

The landscape of obesity treatment continues to evolve rapidly, with two major developments making headlines: the first head-to-head trial comparing Zepbound (tirzepatide) and Wegovy (semaglutide) for weight loss, and Eli Lilly's launch of the innovative Zepbound KwikPen delivery system.

Landmark Trial: SURMOUNT-5 Compares Tirzepatide and Semaglutide

For the first time, researchers have directly compared these two leading weight-loss medications in a randomized controlled trial. The SURMOUNT-5 trial, published in The New England Journal of Medicine in 2025, enrolled 751 adults with obesity but without type 2 diabetes and randomly assigned them to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or semaglutide (1.7 mg or 2.4 mg) once weekly for 72 weeks.

Superior Weight Loss with Tirzepatide

The results demonstrated that tirzepatide achieved significantly greater weight reduction compared to semaglutide. At 72 weeks, participants treated with tirzepatide experienced an average weight loss of 20.2%, compared to 13.7% with semaglutide—a difference of 6.5 percentage points. In absolute terms, this translated to an average loss of 22.8 kg (50.3 pounds) with tirzepatide versus 15.0 kg (33.1 pounds) with semaglutide.

More Patients Achieving Meaningful Weight Loss Targets

The trial also examined how many participants achieved clinically meaningful weight loss thresholds. Tirzepatide-treated patients were significantly more likely to reach these milestones:

- ≥10% weight loss: 81.6% with tirzepatide vs 60.5% with semaglutide

- ≥15% weight loss: 64.6% with tirzepatide vs 40.1% with semaglutide

- ≥20% weight loss: 48.4% with tirzepatide vs 27.3% with semaglutide

- ≥25% weight loss: 31.6% with tirzepatide vs 16.1% with semaglutide

Participants on tirzepatide were 1.3 to 2.0 times more likely to achieve these weight loss targets compared to those on semaglutide.

Real-World Evidence Confirms Trial Findings

These findings align with real-world data published in JAMA Internal Medicine in 2024, which analyzed over 18,000 adults with overweight or obesity who initiated either medication. This large observational study found that at 12 months, tirzepatide was associated with 15.3% weight loss compared to 8.3% with semaglutide—a difference of 6.9 percentage points. Patients on tirzepatide were also significantly more likely to achieve weight loss of ≥5%, ≥10%, and ≥15%.

Similar Safety Profiles

Both medications demonstrated similar safety profiles, with gastrointestinal side effects being the most common adverse events in both groups. These effects were predominantly mild to moderate in severity and occurred primarily during the dose escalation phase. Interestingly, treatment discontinuation due to gastrointestinal events occurred more frequently with semaglutide than with tirzepatide in the SURMOUNT-5 trial.

Introducing the Zepbound KwikPen: A Full Month in One Device

In a significant advancement for patient convenience, Eli Lilly has launched the Zepbound KwikPen, a novel delivery system that provides a full month of treatment in a single device. This innovation addresses one of the practical challenges of chronic weight management therapy: the need for multiple injections and devices.

How the KwikPen Works

The Zepbound KwikPen is designed to deliver four weekly doses from one pen, eliminating the need to manage multiple single-dose pens throughout the month. Patients administer the medication subcutaneously once weekly in the abdomen, thigh, or upper arm, rotating injection sites with each dose. The pen can be used at any time of day, with or without meals.

Dosing and Titration

Zepbound is available in multiple dosage strengths (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg), allowing for individualized dose titration. The recommended starting dose is 2.5 mg once weekly, increased after 4 weeks to 5 mg once weekly. The dose can then be increased in 2.5 mg increments every 4 weeks based on treatment response and tolerability, with 15 mg being the maximum recommended weekly dose.

Patient-Friendly Features

The KwikPen system offers several advantages for patients managing chronic obesity:

- Reduced device burden: One pen replaces four single-dose pens per month

- Simplified storage: Fewer devices to refrigerate and manage

- Consistent delivery: Reliable subcutaneous injection with each use

- Flexibility: Patients can self-administer after proper training

What This Means for Obesity Treatment

These developments represent significant progress in obesity management. The SURMOUNT-5 trial provides the first direct comparison showing tirzepatide's superior efficacy over semaglutide, while the KwikPen launch improves the practical aspects of long-term treatment adherence.

Both tirzepatide and semaglutide work by mimicking incretin hormones that regulate appetite and food intake. Tirzepatide's dual mechanism—activating both GLP-1 and GIP receptors—appears to confer additional weight loss benefits compared to semaglutide's selective GLP-1 receptor activation.

For healthcare providers and patients navigating obesity treatment options, these findings suggest that tirzepatide may offer enhanced weight reduction outcomes, while the new delivery system may improve treatment convenience and adherence. As with all obesity medications, these agents should be used as part of a comprehensive approach that includes dietary modifications and increased physical activity.