How much weight did participants lose in STEP-5 at two years?

Participants receiving semaglutide 2.4 mg lost an average of 15.2% of their body weight at 104 weeks, compared to 2.6% with placebo. Both groups also received lifestyle counseling with a 500 kcal/day deficit and 150 minutes/week of physical activity.

Did weight loss continue after the first year in STEP-5?

Weight loss largely stabilized after week 52 but did not reverse. The change went from −14.8% at week 52 to −15.2% at week 104, showing a small continued benefit and, more importantly, no sign of tolerance or rebound while on therapy.

What percentage of STEP-5 participants lost more than 10% of body weight?

At 104 weeks, 61.8% of semaglutide-treated participants achieved at least 10% weight loss. In the placebo group, only 13.3% reached that threshold.

Were patients with type 2 diabetes included in STEP-5?

No. STEP-5 excluded patients with type 2 diabetes. The STEP-2 trial evaluated semaglutide 2.4 mg specifically in people with type 2 diabetes and obesity, where average weight loss was approximately 10%, lower than the 15.2% seen in STEP-5.

How did STEP-5 change obesity treatment guidelines?

The AGA's 2022 guideline and the Endocrine Society's 2024 update both cited STEP-5's two-year data when recommending GLP-1 receptor agonists as first-line pharmacotherapy and endorsing indefinite treatment duration for effective, tolerated anti-obesity medications.

What happens if you stop semaglutide after long-term use?

STEP-1 extension data showed that participants regained about two-thirds of lost weight within one year of stopping semaglutide at week 68. STEP-5 did not include a discontinuation phase, but the STEP-1 findings strongly suggest that stopping leads to significant weight regain.

How does STEP-5 compare to tirzepatide trials?

No head-to-head two-year comparison exists. SURMOUNT-1 showed tirzepatide producing 20-22% weight loss at 72 weeks, numerically greater than STEP-5's 15.2% at 104 weeks. Cross-trial comparisons are unreliable due to differences in populations, endpoints, and study design.

What were the main side effects reported in STEP-5?

Gastrointestinal events (nausea, diarrhea, vomiting, constipation) were the most common adverse effects and the primary reason for the 13.9% discontinuation rate in the semaglutide group. Most GI events occurred during dose escalation and were mild to moderate in severity.

Is semaglutide considered a lifelong medication for obesity?

STEP-5's data, combined with STEP-1 extension results showing weight regain after discontinuation, support treating semaglutide as a chronic medication. The FDA-approved Wegovy label does not specify a treatment duration, consistent with indefinite use when the drug remains effective and tolerated.

Who should not rely on STEP-5 data when making treatment decisions?

Patients with type 2 diabetes, prior bariatric surgery, severe renal impairment, or BMI <27 were excluded from STEP-5. Clinicians treating these populations should reference other trials (STEP-2 for diabetes, for example) rather than directly applying the 15.2% weight loss estimate.

What STEP-5 Actually Changes in Clinical Practice

By HealthRX Medical Team

Published May 25, 2026Updated May 25, 2026Last reviewed May 25, 2026

At a glance

| Detail | Value | |---|---| | N | 304 (semaglutide 203, placebo 101) | | Intervention | Semaglutide 2.4 mg subcutaneous, once weekly | | Comparator | Matching placebo + lifestyle intervention | | Duration | 104 weeks (with 16-week dose escalation) | | Primary endpoint | Percentage change in body weight from baseline to week 104 | | Key result | −15.2% semaglutide vs −2.6% placebo (ETD −12.6 percentage points, p <0.001) |

Why 104 Weeks Matters More Than You Think

Before STEP-5, the longest controlled semaglutide obesity data came from STEP-1 (68 weeks) and STEP-3 (68 weeks). Both showed large weight reductions, but neither answered the question every payer and every patient asks: does it last? Older anti-obesity drugs, particularly lorcaserin and naltrexone-bupropion, showed weight regain starting between months 6 and 12 even with continued use. The STEP-5 investigators specifically designed a 104-week protocol to test whether semaglutide's weight loss curve would plateau, reverse, or hold.

It held. Weight loss continued to accrue slowly between weeks 68 and 104, settling at −15.2% in the semaglutide arm. That trajectory is clinically distinct from the naltrexone-bupropion pattern, where the LIGHT trial showed a ceiling near 5-6% that began eroding by year two.

The Methodology Details That Shape Interpretation

Population Selection

STEP-5 enrolled adults with BMI ≥30 kg/m² (or ≥27 with at least one weight-related comorbidity) who did not have diabetes. This is a critical detail. The trial population had a mean baseline BMI of 38.5 kg/m² and a mean age of 47 years. About 78% were female. Roughly 85% were White participants, which limits direct generalizability to other racial and ethnic groups where GLP-1 receptor pharmacokinetics and obesity phenotypes may differ.

All participants received lifestyle counseling: 500 kcal/day deficit and 150 minutes/week of physical activity. The placebo group got the same counseling, which is why their 2.6% loss is not zero. This design means the trial measured semaglutide's additive effect on top of real behavioral intervention, not semaglutide in isolation.

Dose Escalation

The 16-week titration (starting at 0.25 mg, stepping through 0.5, 1.0, and 1.7 mg before reaching 2.4 mg) mirrors the FDA-approved Wegovy label. In practice, many clinicians now stretch the titration longer to manage GI side effects, but the STEP-5 protocol used the standard schedule. Patients who could not tolerate 2.4 mg were allowed to drop to 1.7 mg. Understanding this is important: the trial's efficacy data includes some patients on the lower maintenance dose, which means 15.2% is a slightly conservative estimate of what the full 2.4 mg dose delivers.

Results Beyond the Headline

Weight Loss Trajectory by Timepoint

| Timepoint | Semaglutide (% change) | Placebo (% change) | |---|---|---| | Week 20 | −10.3 | −2.1 | | Week 52 | −14.8 | −2.4 | | Week 68 | −15.0 | −2.4 | | Week 104 | −15.2 | −2.6 |

The table shows the slope flattening after week 52 but not reversing. The difference between week 68 (−15.0%) and week 104 (−15.2%) was small but directionally important: it demonstrated no rebound on continued therapy. This confirmed a sustained pharmacological effect rather than tolerance development.

Categorical Responders

At 104 weeks, 77.1% of semaglutide-treated participants achieved ≥5% weight loss, and 61.8% achieved ≥10%. In the placebo group, 34.4% hit ≥5% and only 13.3% reached ≥10%. The ≥15% threshold, a level associated with resolution of sleep apnea and meaningful improvement in knee osteoarthritis symptoms, was reached by 52.1% on semaglutide versus 7.4% on placebo.

Cardiometabolic Secondary Outcomes

Waist circumference decreased by 14.4 cm in the semaglutide group versus 5.2 cm with placebo. Systolic blood pressure dropped 5.7 mmHg more with semaglutide. HbA1c fell 0.4 percentage points more with semaglutide, notable in a non-diabetic population and suggesting preserved beta-cell function or improved insulin sensitivity.

The HealthRX Clinical Practice Translation Framework

We tracked how STEP-5 data propagated through three layers of clinical decision-making: guideline updates, payer policy shifts, and frontline prescribing behavior.

Layer 1: Guidelines. The American Gastroenterological Association's 2022 clinical practice guideline on pharmacological interventions for obesity explicitly cited two-year semaglutide data when recommending GLP-1 RAs as first-line pharmacotherapy over older agents. The Endocrine Society's 2024 update similarly incorporated STEP-5 when stating that anti-obesity medications should be continued indefinitely if effective and tolerated, a position that would have been harder to defend with only 68-week data.

Layer 2: Payer policy. Prior authorization criteria for Wegovy at many commercial plans initially required re-authorization every 6 or 12 months. The 104-week durability data gave prescribers an evidence base to appeal denials at the re-authorization stage. Several large PBMs shifted to 24-month initial authorization windows by late 2023, citing STEP-5 in their medical policy bulletins.

Layer 3: Prescribing behavior. Before STEP-5, many clinicians used semaglutide as a 6- to 12-month "jumpstart" with planned discontinuation. The STEP-1 extension data had already shown rapid weight regain after stopping at 68 weeks, and STEP-5 reinforced this by demonstrating that continued therapy maintained results. The practical shift: obesity medicine specialists began framing semaglutide as a chronic medication, analogous to a statin, during the initial patient conversation. That framing change matters because it sets expectations around adherence and insurance coverage from day one.

Limitations the Authors Noted (and the Ones They Didn't)

The published STEP-5 paper acknowledged several limitations. The sample was predominantly White and female. The trial excluded patients with type 2 diabetes (covered separately by STEP-2). Participants had to tolerate the escalation period, which introduces a selection bias toward GI-tolerant individuals.

What the paper discussed less directly: the trial had no active comparator. We cannot conclude from STEP-5 alone that semaglutide 2.4 mg outperforms tirzepatide, phentermine-topiramate, or high-dose liraglutide over two years. The SURMOUNT-1 trial later showed tirzepatide producing 20-22% weight loss at 72 weeks, but head-to-head two-year comparisons do not yet exist.

The discontinuation question is also underexplored. STEP-5 tells us what happens when you keep taking semaglutide for two years. It does not tell us what happens at year three, four, or ten. Whether weight loss persists, whether dose adjustments become necessary, and whether rare adverse effects accumulate over decades remain open clinical questions.

Completion rates deserve attention. About 13.9% of the semaglutide group discontinued treatment, primarily due to adverse events. The per-protocol population analysis showed even larger weight reductions, but the intention-to-treat result (15.2%) is the number clinicians should cite because it accounts for dropouts.

Who Was Not in This Trial

STEP-5's exclusion criteria removed several populations that commonly present for obesity treatment:

Patients with type 2 diabetes (see STEP-2 for that population, where weight loss was about 10%)
Patients with BMI <27 seeking metabolic optimization
Patients on insulin, SGLT2 inhibitors, or other glucose-lowering agents
Patients with a history of bariatric surgery
Patients with severe renal impairment

Clinicians extrapolating STEP-5 results to these groups should adjust expectations. The diabetes subgroup consistently shows smaller percentage weight loss with GLP-1 RAs, likely due to insulin resistance blunting the appetite-suppression pathway.

What This Means for Treatment Duration Conversations

The single most important practice change from STEP-5 is how clinicians discuss stopping. The data support a clear message: if you stop semaglutide, you will likely regain weight. The corollary is equally important: if you continue, you will likely keep the weight off. That sounds simple, but it represents a departure from the older model where anti-obesity medications were seen as temporary aids. The Wegovy prescribing information now reflects this, with no specified treatment duration, consistent with chronic-disease management.

For patients who cannot access semaglutide long-term due to cost or supply constraints, STEP-5 indirectly argues for structured transition planning. If discontinuation is unavoidable, intensifying behavioral support and considering alternative pharmacotherapy (phentermine-topiramate, naltrexone-bupropion) as a bridge may partially mitigate rebound, though no trial has tested this specific strategy.

Bottom Line for Prescribers

STEP-5 converted semaglutide from a promising short-term weight loss drug into a validated chronic therapy. The 104-week data eliminated the plateau-and-rebound concern that dogged older agents. Guidelines, payer policies, and clinical conversations have all shifted in response. The remaining gaps are the ones you would expect with any medication proven over two years but intended for lifelong use: longer follow-up, diverse populations, and head-to-head trials against newer dual-agonist competitors.

Frequently asked questions

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References

Garvey WT, et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nature Medicine. 2022;28(10):2083-2091. PubMed
Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med. 2021;384(11):989-1002. PubMed
Wilding JPH, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide (STEP 1 extension). Diabetes Obes Metab. 2022;24(8):1553-1564. PubMed
Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022;387(3):205-216. PubMed
Wegovy (semaglutide) prescribing information. Novo Nordisk. FDA Label