Ventralink- •Semaglutide (Wegovy) produces ~34 lbs of weight loss on average — with 1 in 3 patients losing 20% or more of their body weight
- •Tirzepatide (Zepbound) produces ~48 lbs of weight loss — and the head-to-head SURMOUNT-5 trial confirmed it beats semaglutide by about 16 lbs
- •The SELECT trial proved cardiovascular benefits: 20% reduction in heart attacks, strokes, and cardiovascular death in people with obesity
- •Weight regain is real: People who stopped tirzepatide regained ~31 lbs within a year, which is why these medications are often needed long-term
- •These are the largest weight loss trials ever conducted — thousands of patients, followed for years, with rigorous methodology
Before 2021, the best non-surgical weight loss treatments produced only modest results. Then the STEP and SURMOUNT trials changed everything. Here's what those trials actually showed.
The STEP Trials: Semaglutide's Proof
The STEP (Semaglutide Treatment Effect in People with Obesity) program was a series of clinical trials that tested semaglutide 2.4 mg weekly — the dose now sold as Wegovy. Different trials tested the medication in different populations.
STEP 1: Adults Without Diabetes
📊 Who was in this trial? Adults with obesity or overweight without diabetes. Average weight: 232 lbs (105 kg), BMI 38. Most were women (74%) with an average age of 46. About 44% had prediabetes.
STEP 1
2021Semaglutide 2.4 mg (Wegovy)
The headline: Starting at an average of 232 lbs, participants lost 34 lbs (vs 6 lbs with placebo). One-third of patients lost 20% or more of their body weight — a result previously only seen with surgery.
STEP 2: Adults With Type 2 Diabetes
📊 Different population: This separate trial enrolled adults with obesity/overweight who also had type 2 diabetes — an important distinction because diabetes affects how the body responds to weight loss treatments.
STEP 2
2021Semaglutide 2.4 mg (Wegovy)
Important finding: People with type 2 diabetes lost less weight — 22 lbs vs 34 lbs in STEP 1. This is a consistent finding across all weight loss medications and is likely related to how diabetes affects metabolism.
The SURMOUNT Trials: Tirzepatide Steps Up
Shortly after the STEP results, Eli Lilly released results from SURMOUNT — testing tirzepatide, a dual GLP-1/GIP agonist. The results were even more impressive.
📊 Similar population: SURMOUNT-1 participants averaged 231 lbs (105 kg) with a BMI of 38. About 67% were women with an average age of 45. Nearly 60% had prediabetes.
SURMOUNT-1
2022Tirzepatide (Zepbound/Mounjaro)
Record-setting: Starting at an average of 231 lbs, participants on the highest dose (15 mg) lost 48 lbs. Over 1 in 3 patients (36%) lost more than 25% of their body weight — approaching bariatric surgery results without the surgery.
Head-to-Head: The Direct Comparison
For years, we could only compare these medications indirectly by looking at separate trials. Then in 2025, SURMOUNT-5 gave us the first direct head-to-head comparison.
SURMOUNT-5
2025Tirzepatide vs. Semaglutide (head-to-head)
The verdict: Tirzepatide produced 47 lbs of weight loss vs. 31 lbs with semaglutide — about 16 lbs more. This confirms what the earlier trials suggested: tirzepatide produces more weight loss on average.
| Metric | Wegovy (Semaglutide) | Zepbound (Tirzepatide) |
|---|---|---|
| Average weight loss (SURMOUNT-5) | 31 lbs | 47 lbs |
| Lost ≥20% body weight | ~32% | ~57% |
| Lost ≥10% body weight | ~69% | ~91% |
| Time to reach max dose | 16 weeks | 20 weeks |
| Cardiovascular outcomes data | Yes (SELECT trial) | Pending (SURMOUNT-MMO, expected 2027) |
💡 What This Means for You
Both medications produce clinically meaningful weight loss. Tirzepatide produces about 16 lbs more weight loss on average than semaglutide.
But semaglutide has proven cardiovascular benefits (SELECT trial) and longer real-world experience. Your doctor will also consider cost, insurance coverage, and your individual health profile. Either medication represents a major advance over previous options.
The SELECT Trial: Beyond Weight Loss
For years, the question was: Does weight loss from medications actually improve health outcomes, or just the number on the scale?
The SELECT trial answered that question definitively.
SELECT
2023Semaglutide 2.4 mg (Wegovy)
SELECT enrolled patients with obesity and established heart disease, but without diabetes. The goal wasn't just weight loss — it was to see if the medication prevented heart attacks, strokes, and death.
📊 Different population: SELECT patients were older (average age 62) and mostly male (72%). They had established cardiovascular disease and a lower average BMI of 33. This was a higher-risk group designed to detect cardiovascular outcomes.
❤️ SELECT Trial Results: Cardiovascular Outcomes
(heart attack, stroke, CV death)
(fatal and non-fatal)
This was the first trial to prove that a weight loss medication reduces cardiovascular events. It's why the FDA expanded Wegovy's approval to include cardiovascular risk reduction in people with obesity and heart disease.
What Happens When You Stop?
One of the most important — and sobering — findings comes from STEP 1's extension phase and the SURMOUNT-4 trial.
SURMOUNT-4
2023Tirzepatide (Zepbound)
The withdrawal effect: After 36 weeks on tirzepatide (losing ~48 lbs), half the patients continued the medication and half switched to placebo. Those who stopped regained about 31 lbs over the next year. Those who continued lost an additional 12 lbs.
⚠️ The Weight Regain Reality
Most people who stop these medications regain a significant portion of the weight they lost — typically about two-thirds within a year.
This isn't a personal failure. It's biology. Obesity is a chronic condition, and just like blood pressure medications, weight loss medications often need to be continued to maintain their effects.
This is why doctors increasingly think of these as long-term treatments, not short-term fixes.
Putting It All Together
Here's what the collective evidence tells us:
These medications work. The average patient loses 34-48 lbs depending on the medication. That's not a fad diet result. That's transformative.
The benefits go beyond the scale. Blood pressure drops. Blood sugar improves. Inflammation decreases. And for semaglutide, we now have proof of fewer heart attacks and strokes.
They're not magic pills. About 10-15% of people don't respond well. Side effects are common (more on that in the next article). And most people need to stay on them long-term.
But for the right person, they're the most effective non-surgical tools we've ever had.
📊 Trial Quality Matters
All the trials discussed here were large, randomized, placebo-controlled, and double-blinded — the gold standard for medical evidence. They were published in top journals like the New England Journal of Medicine and JAMA.
When you hear about "promising new weight loss treatments," ask: Is the evidence this strong? For these medications, the answer is yes.