STEP Trials Decoded: What 15% Weight Loss Actually Means

When Novo Nordisk announced that semaglutide produced "15% weight loss" in clinical trials, headlines exploded. But what does that number actually mean? Who achieved it? Who didn't? And what happened after two years?

The STEP (Semaglutide Treatment Effect in People with obesity) trial program is the most comprehensive weight loss medication research ever conducted. Understanding these trials—really understanding them—helps you set realistic expectations, recognize what success looks like, and know what to discuss with your provider.

This is a deep dive. We're going beyond the headlines to examine what the data actually shows.

The STEP Program: An Overview

The STEP program consists of multiple large-scale trials designed to test semaglutide 2.4mg (now marketed as Wegovy) across different populations. Each trial asked different questions:

Additional trials examined teens (STEP TEENS), people with heart failure (STEP-HFpEF), and cardiovascular outcomes (SELECT). Together, these trials enrolled over 25,000 participants.

STEP 1: The Numbers Everyone Cites

STEP 1 enrolled 1,961 adults without diabetes who had BMI ≥30 (or ≥27 with at least one weight-related condition). Participants were randomized 2:1 to receive semaglutide 2.4mg weekly or placebo, alongside lifestyle intervention (counseling on diet, 150 minutes weekly activity).

Here's what actually happened:

The "Intention-to-Treat" vs "On-Treatment" Distinction

Here's where it gets nuanced. The 14.9% figure is the "intention-to-treat" (ITT) result—it includes everyone randomized to semaglutide, even those who dropped out or didn't take the medication consistently. This is the conservative, real-world-applicable number.

The "trial product estimand" (people who actually took the medication as directed) achieved 16.9% weight loss. This represents what you might expect if you tolerate the medication and stick with it.

The difference matters: if you're someone who can tolerate semaglutide and stay on it, you're likely looking at the higher number. If you're uncertain about tolerability, the lower number is more realistic for planning.

Responder Rates: Who Achieves What

Averages hide individual variation. The responder analysis tells a more complete story:

Compare this to placebo: only 31.5% lost ≥5%, and just 12% lost ≥10%.

What this tells us: The vast majority of people on semaglutide achieve clinically meaningful weight loss (≥5%). About half achieve what would be considered "excellent" response (≥15%). About one-third achieve weight loss that rivals bariatric surgery outcomes (≥20%).

But it also means roughly 14% don't achieve even 5% loss—these are the "non-responders" we'll discuss later.

STEP 2: When Diabetes Is Part of the Picture

Type 2 diabetes complicates weight loss. Diabetes medications (especially insulin and sulfonylureas) can promote weight gain. Metabolic dysfunction may impair weight loss response. STEP 2 asked: does semaglutide still work?

The weight loss is lower than STEP 1—about 10% versus 15%—but still substantial and consistent. The A1C reduction of 1.6 percentage points is clinically meaningful; many participants reduced or eliminated other diabetes medications.

STEP 3: What If You Add Intensive Behavioral Support?

STEP 3 combined semaglutide with an intensive lifestyle program: an initial 8-week low-calorie diet (1,000-1,200 kcal/day with meal replacements), followed by conventional diet, plus 30 individual dietitian sessions over 68 weeks.

Results: 16.0% weight loss with semaglutide versus 5.7% with placebo (both groups received the intensive intervention).

Interestingly, this isn't dramatically better than STEP 1's 14.9%—suggesting that the medication does most of the heavy lifting. The behavioral intervention helped the placebo group achieve better-than-usual results (5.7% vs 2.4% in STEP 1), but didn't dramatically amplify semaglutide's effects.

What this means for you: intensive behavioral programs can help, but they're not required to achieve good results with semaglutide. The medication provides substantial benefit even with basic lifestyle counseling.

STEP 4: The Critical "What Happens If I Stop?" Data

STEP 4 is perhaps the most important trial for understanding GLP-1 medications as long-term treatment. Everyone started on semaglutide. After 20 weeks (when they'd lost significant weight), participants were randomized to either continue semaglutide or switch to placebo for another 48 weeks.

The results are sobering but essential:

Those who continued semaglutide kept losing weight (from -10.6% at week 20 to -17.4% at week 68). Those who switched to placebo regained about two-thirds of their lost weight within 48 weeks.

This data is crucial for informed decision-making. Going into GLP-1 treatment expecting it to be temporary sets you up for disappointment. Understanding it as ongoing medical management—like blood pressure medication—creates realistic expectations.

STEP 5: Two-Year Durability Data

STEP 5 provides the longest published data on semaglutide for weight management: 104 weeks (2 years). This trial enrolled 304 adults without diabetes.

The pattern is revealing: weight loss plateaus around week 60-68, then maintains through week 104. Participants didn't continue losing after the first year, but they didn't regain either. The 15.2% loss at two years is essentially identical to the ~15% at one year.

This confirms durability but also suggests that what you achieve in the first year is approximately what you'll maintain—there's no additional loss from continued treatment beyond the plateau.

STEP TEENS: Even Better Results in Adolescents

STEP TEENS enrolled 201 adolescents (ages 12-17) with obesity. The results surprised many researchers:

Notably, adolescents achieved greater BMI reduction than adults—16.1% versus adults' 14.9%. Even more striking: 44.9% of teens who started in the obese category moved below the obesity threshold, and 25% achieved a healthy weight.

The better response in teens may reflect more metabolic flexibility, fewer years of metabolic dysfunction, or other factors. It's promising for adolescents struggling with obesity, though long-term safety data in growing bodies remains limited.

SELECT: The Cardiovascular Game-Changer

The SELECT trial (17,604 participants over nearly 4 years) wasn't primarily about weight loss—it was about whether weight loss from semaglutide could prevent heart attacks, strokes, and cardiovascular death.

The answer: definitively yes.

The 20% reduction in major adverse cardiovascular events (MACE) was statistically significant and clinically meaningful. This led to FDA approval of Wegovy specifically for cardiovascular risk reduction in patients with established heart disease and overweight/obesity.

Importantly, analysis showed only about one-third of the cardiovascular benefit was explained by waist circumference reduction—suggesting semaglutide has direct cardioprotective effects beyond weight loss. This transforms how we think about the medication: it's not just about getting smaller, it's about cardiovascular protection.

Beyond Weight: Cardiometabolic Improvements

Across STEP trials, semaglutide improved multiple health markers:

Marker	Semaglutide Change	Placebo Change
Waist circumference	-13.5 cm	-4.1 cm
Systolic blood pressure	-6.2 mmHg	-1.1 mmHg
HbA1c (non-diabetic)	-0.5%	-0.2%
LDL cholesterol	-4.0%	+0.5%
Triglycerides	-22.0%	-7.0%
C-reactive protein	-55%	-19%

The C-reactive protein (CRP) reduction—a marker of inflammation—was particularly striking. Chronic inflammation contributes to heart disease, diabetes, and other conditions. A 55% reduction represents meaningful improvement in metabolic health beyond the scale.

Side Effects: The Full Picture

The STEP trials documented comprehensive safety data:

The most common side effects were gastrointestinal: nausea (44%), diarrhea (30%), vomiting (24%), and constipation (24%). These were typically mild-to-moderate and most common during dose escalation.

About 7% of participants discontinued due to adverse events—meaning 93% tolerated the medication well enough to continue. Serious adverse events were rare and similar between semaglutide and placebo groups.

The STEP 1 Extension: What Happens After the Trial?

An often-overlooked follow-up to STEP 1 tracked participants after the trial ended—when everyone stopped medication. The results echo STEP 4:

After stopping semaglutide, participants regained approximately two-thirds of lost weight within one year. Net weight loss dropped from 17.3% at week 68 to just 5.6% at week 120 (one year after stopping).

Cardiometabolic improvements also reversed: blood pressure, lipids, and inflammatory markers returned toward baseline.

This extension data reinforces that GLP-1 medications treat an ongoing condition rather than providing a permanent fix. Like stopping blood pressure medication, stopping GLP-1s allows the underlying condition to reassert itself.

Putting It All Together: What the STEP Trials Mean for You

Realistic Expectations

• Most people (86%) achieve clinically meaningful weight loss (≥5%)
• About half achieve excellent response (≥15%)
• About one-third achieve surgical-level outcomes (≥20%)
• 10-14% are non-responders (<5% loss)
• Weight loss plateaus around 12-15 months, then maintains
• Stopping leads to regain of approximately two-thirds of lost weight

Factors That May Affect Your Response

• Diabetes: Expect ~10% loss vs ~15% without diabetes
• Age: Adolescents may respond better than adults
• Duration: Most weight loss occurs in first year
• Adherence: Those who stick with it achieve ~17% vs ~15% average

The Big Picture

The STEP trials established semaglutide as the most effective pharmaceutical weight loss treatment ever studied. The 15% average weight loss is roughly three times what older medications achieved. The cardiovascular benefits extend value beyond weight management alone.

But the trials also reveal important limitations: this is likely lifelong treatment, some people don't respond, and the medication doesn't eliminate the need for lifestyle attention. Understanding both the power and the limitations helps you make informed decisions and set appropriate expectations.