What was the primary endpoint of the STEP-5 trial?

The primary endpoint was the percentage change in body weight from baseline to week 104. Semaglutide 2.4 mg produced a mean reduction of 15.2% compared to 2.6% with placebo (estimated treatment difference −12.6 percentage points; 95% CI −15.3 to −9.8; p <0.0001).

How many participants completed the full 104 weeks of STEP-5?

Approximately 85% of semaglutide-treated participants and a similar proportion in the placebo arm completed the 104-week treatment period. The most common reason for early discontinuation in the semaglutide group was gastrointestinal adverse events.

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

Weight loss was largely achieved by week 60 and then plateaued through week 104. There was no clinically meaningful regain while participants remained on semaglutide. Most of the reduction occurred in the first 40 weeks.

What percentage of patients lost at least 20% body weight on semaglutide in STEP-5?

Under the treatment-policy estimand, 36.1% of semaglutide-treated participants achieved ≥20% body weight loss at 104 weeks. Under the on-treatment estimand, this rose to 39.3%.

What were the most common side effects in STEP-5?

Gastrointestinal events were most frequent: nausea (58.6%), diarrhea (36.2%), constipation (34.2%), and vomiting (29.6%). Most symptoms were mild to moderate and occurred during the dose-escalation phase. Only 7.2% discontinued due to adverse events.

Did STEP-5 include patients with type 2 diabetes?

No. Participants with type 2 diabetes were excluded from STEP-5. The STEP-2 trial evaluated semaglutide 2.4 mg specifically in adults with type 2 diabetes and overweight or obesity, though that trial ran for only 68 weeks.

How does STEP-5 compare to STEP-1 in terms of weight loss?

STEP-5 showed a slightly larger mean weight reduction (15.2% at 104 weeks) compared to STEP-1 (12.4% at 68 weeks). The additional weight loss between months 16 and 24 suggests a slow continued effect beyond what was captured in the shorter trial.

What happens after stopping semaglutide based on STEP program data?

STEP-5 itself did not include a post-treatment washout phase. However, the STEP-1 extension study and the STEP-4 trial both demonstrated significant weight regain after discontinuation, with participants recovering roughly two-thirds of lost weight within a year of stopping.

Is the STEP-5 trial the basis for the Wegovy FDA approval?

The FDA approved Wegovy (semaglutide 2.4 mg) in June 2021, primarily based on the STEP-1, STEP-2, and STEP-3 trials. STEP-5 was published later (2022) and contributed to the long-term durability evidence supporting continued prescribing.

Were there cardiovascular benefits shown in STEP-5?

STEP-5 was not powered for cardiovascular outcomes. It did show improvements in systolic blood pressure, waist circumference, and inflammatory markers. Cardiovascular event reduction was later demonstrated in the separate SELECT trial, which used the same semaglutide dose in patients with established cardiovascular disease.

STEP-5 Results in Detail: Numbers, Subgroups, and Time Course

Q: How many participants completed the full 104 weeks of STEP-5?

Approximately 85% of semaglutide-treated participants and a similar proportion in the placebo arm completed the 104-week treatment period. The most common reason for early discontinuation in the semaglutide group was gastrointestinal adverse events.

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

Weight loss was largely achieved by week 60 and then plateaued through week 104. There was no clinically meaningful regain while participants remained on semaglutide. Most of the reduction occurred in the first 40 weeks.

Q: What percentage of patients lost at least 20% body weight on semaglutide in STEP-5?

Under the treatment-policy estimand, 36.1% of semaglutide-treated participants achieved ≥20% body weight loss at 104 weeks. Under the on-treatment estimand, this rose to 39.3%.

Q: What were the most common side effects in STEP-5?

Gastrointestinal events were most frequent: nausea (58.6%), diarrhea (36.2%), constipation (34.2%), and vomiting (29.6%). Most symptoms were mild to moderate and occurred during the dose-escalation phase. Only 7.2% discontinued due to adverse events.

Q: Did STEP-5 include patients with type 2 diabetes?

No. Participants with type 2 diabetes were excluded from STEP-5. The STEP-2 trial evaluated semaglutide 2.4 mg specifically in adults with type 2 diabetes and overweight or obesity, though that trial ran for only 68 weeks.

Q: How does STEP-5 compare to STEP-1 in terms of weight loss?

STEP-5 showed a slightly larger mean weight reduction (15.2% at 104 weeks) compared to STEP-1 (12.4% at 68 weeks). The additional weight loss between months 16 and 24 suggests a slow continued effect beyond what was captured in the shorter trial.

Q: What happens after stopping semaglutide based on STEP program data?

STEP-5 itself did not include a post-treatment washout phase. However, the STEP-1 extension study and the STEP-4 trial both demonstrated significant weight regain after discontinuation, with participants recovering roughly two-thirds of lost weight within a year of stopping.

Q: Is the STEP-5 trial the basis for the Wegovy FDA approval?

The FDA approved Wegovy (semaglutide 2.4 mg) in June 2021, primarily based on the STEP-1, STEP-2, and STEP-3 trials. STEP-5 was published later (2022) and contributed to the long-term durability evidence supporting continued prescribing.

Q: Were there cardiovascular benefits shown in STEP-5?

STEP-5 was not powered for cardiovascular outcomes. It did show improvements in systolic blood pressure, waist circumference, and inflammatory markers. Cardiovascular event reduction was later demonstrated in the separate SELECT trial, which used the same semaglutide dose in patients with established cardiovascular disease.

By HealthRX Medical Team

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

At a glance

| Parameter | Detail | |---|---| | N | 304 (semaglutide 152, placebo 152) | | Population | Adults with BMI ≥30 kg/m², or ≥27 kg/m² with at least one weight-related comorbidity | | Intervention | Subcutaneous semaglutide 2.4 mg once weekly | | Comparator | Matched placebo injection once weekly | | Background therapy | Lifestyle intervention (diet counseling + 150 min/week physical activity) in both arms | | Duration | 104 weeks (2 years) | | Primary endpoint | Percent change in body weight from baseline to week 104 | | Key result | −15.2% semaglutide vs −2.6% placebo (ETD −12.6 pp; 95% CI −15.3 to −9.8; p <0.0001) | | Registration | NCT03693430 |

Why STEP-5 Matters Among GLP-1 Trials

The earlier STEP-1 trial ran for 68 weeks and showed a 12.4% mean weight reduction with semaglutide 2.4 mg. Clinicians immediately asked: does that loss hold, grow, or rebound after the first year? STEP-5 was designed to answer exactly that question by extending treatment to 104 weeks with the same dose, the same lifestyle counseling, and a comparable patient population.

This makes STEP-5 the longest placebo-controlled dataset for once-weekly semaglutide 2.4 mg in obesity. Prior GLP-1 receptor agonist studies (liraglutide 3.0 mg in SCALE Maintenance, for instance) suggested partial weight regain after 56 weeks. STEP-5 tested whether the newer, more potent analogue could sustain losses through a full two years of continuous therapy.

Primary Endpoint: Percent Change in Body Weight at Week 104

The primary analysis used a treatment-policy estimand (intention-to-treat, including data after treatment discontinuation or rescue medication) and a trial-product estimand (on-treatment, excluding post-discontinuation data).

Weight Loss by Estimand

| Estimand | Semaglutide 2.4 mg | Placebo | ETD (95% CI) | p-value | |---|---|---|---|---| | Treatment-policy (ITT-like) | −15.2% | −2.6% | −12.6 pp (−15.3 to −9.8) | <0.0001 | | Trial-product (on-treatment) | −16.7% | −2.1% | −14.7 pp (−17.4 to −11.9) | <0.0001 |

The treatment-policy estimate is the more conservative of the two because it includes participants who stopped semaglutide and regained weight. The trial-product estimate reflects what happened to those who stayed on the drug. The gap between −15.2% and −16.7% tells us something important: early discontinuers partially diluted the ITT result, but not dramatically. Roughly 85% of semaglutide participants completed the full 104 weeks.

Mean baseline body weight was approximately 106 kg in both groups. A 15.2% loss translates to roughly 16.1 kg (about 35.5 lbs) of absolute weight reduction from baseline.

Categorical Weight-Loss Thresholds

The trial pre-specified several clinically relevant thresholds. These matter because cardiometabolic risk reductions are typically benchmarked at 5%, 10%, 15%, and 20% body weight loss in obesity treatment guidelines from the AHA/ACC/TOS.

Proportion Achieving Weight-Loss Thresholds (Treatment-Policy Estimand)

| Threshold | Semaglutide 2.4 mg | Placebo | Odds Ratio (95% CI) | |---|---|---|---| | ≥5% weight loss | 77.1% | 34.4% | 6.9 (4.1 to 11.7) | | ≥10% weight loss | 61.8% | 13.2% | 10.4 (5.8 to 18.7) | | ≥15% weight loss | 52.0% | 7.2% | 14.7 (7.1 to 30.3) | | ≥20% weight loss | 36.1% | 3.3% | 16.8 (6.7 to 42.3) |

More than half the semaglutide group lost ≥15% of baseline body weight. More than a third lost ≥20%. The placebo group's 34.4% rate at ≥5% reflects the lifestyle intervention alone, which is consistent with diet-and-exercise benchmarks from prior literature.

Under the trial-product estimand, categorical responder rates were even higher: 83.5% at ≥5%, 68.8% at ≥10%, 56.0% at ≥15%, and 39.3% at ≥20%.

Time-Course Pattern: When Did Weight Loss Plateau?

The published weight-over-time curves show a distinct kinetic pattern. Weight loss was rapid from weeks 0 to 20 (the dose-escalation and early maintenance phase), continued at a slower pace through approximately week 60, then reached a broad plateau that persisted through week 104.

Approximate Trajectory (Semaglutide Arm, Treatment-Policy Estimand)

| Time Point | Mean % Weight Change | |---|---| | Week 20 | −10% | | Week 40 | −14% | | Week 60 | −15.5% | | Week 80 | −15.4% | | Week 104 | −15.2% |

The slight numerical uptick from week 60 (−15.5%) to week 104 (−15.2%) is within normal measurement variability and is not statistically meaningful. The practical takeaway: once-weekly semaglutide 2.4 mg produces most of its weight reduction within the first year, and that loss remains stable through year two with ongoing treatment. There was no late-phase rebound while patients remained on therapy.

The placebo arm showed a modest initial decline (approximately −3% to −4% at week 20, driven by the lifestyle counseling), followed by gradual regain. By week 104, placebo participants had returned to −2.6% from baseline.

Secondary Cardiometabolic Endpoints

STEP-5 measured standard cardiometabolic markers as pre-specified secondary endpoints.

Cardiometabolic Outcomes at Week 104

| Parameter | Semaglutide 2.4 mg (change from baseline) | Placebo (change from baseline) | |---|---|---| | Waist circumference | −14.4 cm | −4.2 cm | | Systolic blood pressure | −5.7 mmHg | −1.6 mmHg | | HbA1c (in non-diabetic participants) | −0.3% | −0.1% | | Fasting glucose | Decreased | Minimal change | | C-reactive protein | Decreased | Minimal change | | Lipid panel (triglycerides) | Improved | Minimal change |

The 14.4 cm waist circumference reduction is clinically notable. Visceral adiposity, as measured by waist circumference, tracks cardiovascular risk more closely than BMI alone, per AHA/ACC guidelines. The systolic blood pressure reduction of approximately 4 mmHg beyond placebo, while modest in absolute terms, is consistent across the STEP program and was later supported by the cardiovascular outcome data from the SELECT trial.

Response Distribution: Not Every Patient Responds Equally

Mean values mask a wide distribution of individual responses. In STEP-5, the semaglutide arm showed meaningful variability.

Approximately 23% of semaglutide-treated participants did not reach the 5% threshold after 104 weeks. This includes both biological non-responders and individuals who discontinued treatment early for adverse events (primarily gastrointestinal). At the other extreme, over a third achieved ≥20% body weight loss, a range that begins to overlap with some bariatric surgery outcomes.

This distribution matters clinically. A prescriber should set expectations: the "average" patient loses about 15%, but roughly one in four may not see clinically meaningful results, while another one in three may lose 20% or more. The trial did not publish formal responder-curve percentile data (e.g., 25th/75th percentile bands), but the categorical thresholds provide a reasonable picture of the spread.

Adverse Events and Discontinuation

Gastrointestinal events were the most common treatment-emergent adverse events, consistent with GLP-1 receptor agonist class effects.

Key Safety Data

| Event | Semaglutide 2.4 mg | Placebo | |---|---|---| | Any GI adverse event | 82.2% | 53.9% | | Nausea | 58.6% | 23.0% | | Diarrhea | 36.2% | 21.7% | | Constipation | 34.2% | 12.5% | | Vomiting | 29.6% | 7.9% | | Discontinued due to AEs | 7.2% | 3.3% |

Most gastrointestinal symptoms were mild to moderate in severity and occurred during the 16-week dose-escalation phase. The 7.2% discontinuation rate for adverse events is relatively low for a 104-week trial. For context, the Wegovy prescribing information reports similar GI event rates across the STEP program.

No new safety signals emerged between weeks 68 and 104 compared to shorter STEP trials. Gallbladder-related events (cholelithiasis, cholecystitis) occurred at numerically higher rates with semaglutide, consistent with rapid weight loss from any cause.

Limitations the Authors Acknowledged

The STEP-5 investigators noted several limitations worth highlighting:

Sample size. At N = 304, STEP-5 was smaller than STEP-1 (N = 1,961). This limits subgroup analysis power (by age, sex, baseline BMI, race/ethnicity).
Population homogeneity. The trial enrolled predominantly White participants (approximately 84%). Representation of Black, Hispanic, and Asian populations was limited, which constrains generalizability.
No diabetes. Participants with type 2 diabetes were excluded. STEP-2 addressed that population separately but only ran for 68 weeks.
No post-treatment follow-up. STEP-5 did not include a randomized withdrawal phase. STEP-1's extension data and the separate STEP-4 trial (which randomized to continued semaglutide vs. switch to placebo at week 20) demonstrated significant weight regain after discontinuation. STEP-5 cannot tell us what happens when the drug is stopped after two years.
Lifestyle intervention floor. Both arms received counseling. In real-world practice, adherence to lifestyle changes varies substantially, which may shift absolute results in either direction.

STEP-5 in the Context of the Broader Program

STEP-5's 104-week data sits between the shorter STEP-1/STEP-3 trials and the cardiovascular outcomes data from SELECT (which ran for a median of 39.8 months but used a different patient population with established cardiovascular disease). The weight-loss magnitude in STEP-5 (−15.2%) is slightly higher than STEP-1's 68-week result (−12.4%), suggesting continued slow accumulation of weight loss between months 16 and 24 in those who remain on therapy.

The trial also predates the tirzepatide SURMOUNT program, which reported weight losses of 20.9% at 72 weeks with the highest tirzepatide dose. Direct cross-trial comparisons require caution due to population and design differences, but STEP-5 remains the longest controlled semaglutide monotherapy dataset available for weight management.

Frequently asked questions

›

References

Garvey WT, Batterham RL, Bhatt DL, et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med. 2022;28(10):2083-2091. PubMed
Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med. 2021;384(11):989-1002. PubMed
Wegovy (semaglutide) prescribing information. Novo Nordisk. Revised 2023. FDA Label
Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults. Circulation. 2014;129(25 Suppl 2):S102-S138. PubMed
Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022;387(3):205-216. PubMed