How much more weight did semaglutide produce versus liraglutide in STEP-8?

Semaglutide 2.4 mg produced 15.8% body weight loss compared to 6.4% with liraglutide 3.0 mg at 68 weeks. The estimated treatment difference was 9.4 percentage points (95% CI: 12.0 to 6.8), meaning semaglutide roughly doubled the efficacy of liraglutide in this head-to-head comparison.

Was STEP-8 blinded or open-label?

STEP-8 used an open-label design for the semaglutide versus liraglutide comparison but was double-blinded for each active agent versus its matched placebo. Participants and investigators knew whether they received semaglutide or liraglutide, which is a limitation acknowledged by the authors.

What percentage of semaglutide patients lost at least 20% body weight?

In the STEP-8 trial, 38.5% of semaglutide-treated patients achieved ≥20% weight loss at 68 weeks, compared to only 6.0% of liraglutide patients. The odds ratio was 10.5 (95% CI: 4.4 to 25.0) favoring semaglutide.

How quickly did the weight loss difference appear between semaglutide and liraglutide?

Visible separation between the two weight-loss curves emerged by week 8. By week 20, semaglutide patients had lost approximately 10% versus 5% for liraglutide. The gap continued widening through the full 68-week treatment period.

Did more patients drop out of the liraglutide arm?

Yes. Treatment discontinuation was 27.6% with liraglutide versus 13.5% with semaglutide. The higher dropout likely reflects daily injection burden and GI intolerance during liraglutide's shorter 4-week titration compared to semaglutide's 16-week escalation.

Does STEP-8 show what happens after stopping semaglutide?

During the 7-week off-treatment follow-up, both groups regained weight. Semaglutide's regain was proportionally steeper, consistent with other STEP program extension data showing that weight maintenance requires continued therapy.

How does STEP-8 compare to the STEP-1 results for semaglutide?

STEP-8's semaglutide arm showed 15.8% weight loss at 68 weeks, slightly lower than STEP-1's 14.9% at the same timepoint (noting STEP-1 used placebo comparison only). The consistency across trials supports reproducibility of the effect size.

Who was enrolled in the STEP-8 trial?

338 adults with BMI ≥30 (or ≥27 with comorbidity) were randomized. The population was 78% female, 83% White, with mean baseline BMI around 37 kg/m². Mean age was approximately 49 years. All received lifestyle intervention counseling.

Is semaglutide now considered first-line over liraglutide for obesity?

Based partly on STEP-8, the 2022 AGA guidelines position semaglutide 2.4 mg as a preferred first-line pharmacotherapy for obesity. Liraglutide remains FDA-approved but is generally considered when semaglutide is unavailable or not tolerated.

STEP-8 Results in Detail: Numbers, Subgroups, and Time Course

Q: Were gastrointestinal side effects worse with semaglutide?

Semaglutide had numerically higher nausea (44.2% vs 38.6%) and vomiting (24.0% vs 14.2%) rates, but fewer patients discontinued due to adverse events (3.2% vs 12.6% for liraglutide). The slower titration schedule allows more adaptation to GI symptoms.

By HealthRX.com Medical Team

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

Clinical image for STEP-8 Results in Detail: Numbers, Subgroups, and Time Course Image: HealthRX.com clinical image

At a glance

| Parameter | Detail | |-----------|--------| | N | 338 randomized (126 semaglutide, 127 liraglutide, 85 placebo) | | Intervention | Semaglutide 2.4 mg subcutaneous once weekly | | Comparator | Liraglutide 3.0 mg subcutaneous once daily | | Duration | 68 weeks (plus 7-week follow-up) | | Primary endpoint | Percentage change in body weight from baseline at week 68 | | Key result | −15.8% (sema) vs −6.4% (lira); ETD −9.4 pp (95% CI: −12.0 to −6.8) |

Primary Endpoint: Weight Change at 68 Weeks

The STEP-8 trial randomized adults with BMI ≥30 (or ≥27 with at least one weight-related comorbidity) to semaglutide 2.4 mg weekly, liraglutide 3.0 mg daily, or placebo, all with lifestyle intervention. The primary estimand used a treatment-policy approach, meaning all participants were analyzed regardless of whether they stayed on drug.

Estimated mean body weight change at week 68:

| Arm | Mean % change (SE) | Absolute kg lost (mean) | |-----|-------------------|------------------------| | Semaglutide 2.4 mg | −15.8% (1.0) | −15.3 kg | | Liraglutide 3.0 mg | −6.4% (0.9) | −6.8 kg | | Placebo | −1.9% (1.2) | −1.8 kg |

The estimated treatment difference (ETD) for semaglutide versus liraglutide was −9.4 percentage points (95% CI: −12.0 to −6.8; P <0.001). Against placebo, semaglutide achieved an ETD of −13.9 pp (95% CI: −16.9 to −10.9), while liraglutide versus placebo reached −4.5 pp (95% CI: −7.4 to −1.6).

These results establish that semaglutide's weight-lowering effect is not simply a class effect of GLP-1 receptor agonism. The magnitude of separation, nearly 2.5-fold greater weight loss, suggests pharmacokinetic and receptor-binding differences between the two molecules translate into clinically distinct outcomes.

Secondary Endpoints and Categorical Responders

The trial pre-specified a categorical responder framework that reveals the distribution of outcomes more clearly than mean values alone:

Categorical Weight Loss Thresholds at Week 68

| Threshold | Semaglutide | Liraglutide | Odds Ratio (95% CI) | |-----------|-------------|-------------|---------------------| | ≥5% weight loss | 87.2% | 58.1% | 5.0 (2.7 to 9.3) | | ≥10% weight loss | 70.9% | 25.6% | 7.9 (4.4 to 14.2) | | ≥15% weight loss | 55.6% | 12.0% | 9.8 (5.0 to 19.0) | | ≥20% weight loss | 38.5% | 6.0% | 10.5 (4.4 to 25.0) |

The odds ratios widen at higher thresholds. More than one in three semaglutide-treated patients lost ≥20% of body weight. Among liraglutide patients, only 1 in 17 crossed that mark. This distribution pattern indicates semaglutide shifts the entire response curve rightward rather than simply pulling the mean via a few extreme responders.

Waist Circumference and Cardiometabolic Markers

Secondary continuous outcomes at week 68:

| Marker | Semaglutide (change) | Liraglutide (change) | ETD (95% CI) | |--------|---------------------|---------------------|--------------| | Waist circumference | −13.5 cm | −6.7 cm | −6.9 cm (−9.2 to −4.5) | | Systolic BP | −5.6 mmHg | −1.6 mmHg | −4.0 mmHg (−7.3 to −0.7) | | HbA1c | −0.2% | −0.1% | −0.1% (NS) | | Fasting glucose | −6.5 mg/dL | −2.2 mg/dL | −4.3 mg/dL | | C-reactive protein | −45.2% | −21.3% | Significant | | Triglycerides | −18.5% | −5.3% | Significant |

The waist circumference difference of nearly 7 cm is clinically relevant because visceral adiposity reduction tracks with cardiovascular risk independent of total weight. The CRP reduction suggests anti-inflammatory effects beyond what weight loss alone predicts, consistent with data from the SELECT cardiovascular outcomes trial published subsequently.

Time-Course Analysis: When Does the Separation Emerge?

Weight loss trajectories showed meaningful divergence beginning at week 8. By week 20, semaglutide patients had lost approximately 10% while liraglutide patients had lost approximately 5%. The separation continued widening through week 52 and remained apparent through the final assessment at week 68.

Semaglutide's weight loss curve did not plateau by week 68, suggesting the 68-week endpoint may underestimate maximal efficacy. Liraglutide's curve, by contrast, showed near-plateau behavior between weeks 40 and 68. This differential trajectory pattern was not pre-specified as an endpoint but has clinical implications for duration of therapy decisions and patient counseling regarding expected timelines.

During the 7-week off-treatment follow-up period (weeks 68 to 75), both groups regained weight, but the semaglutide group's regain was proportionally steeper, consistent with findings from the STEP-1 extension data showing weight regain after discontinuation.

Dose Escalation and Treatment Adherence

Semaglutide was titrated from 0.25 mg weekly to the target 2.4 mg over 16 weeks. Liraglutide was titrated from 0.6 mg daily to 3.0 mg over 4 weeks. This difference in escalation period means the two drugs reached full therapeutic dose at different timepoints, yet the weight-loss separation preceded full semaglutide dosing, appearing as early as week 8 (when semaglutide was still at 1.0 mg).

Treatment discontinuation rates:

Semaglutide: 13.5% discontinued treatment
Liraglutide: 27.6% discontinued treatment
Placebo: 17.6% discontinued treatment

The 2-fold higher discontinuation rate with liraglutide likely reflects both the daily injection burden and the higher rate of persistent GI side effects during the shorter escalation window. The FDA prescribing information for Saxenda notes that patients who cannot tolerate 3.0 mg should discontinue, while semaglutide's longer titration allows more GI adaptation.

Gastrointestinal Tolerability Comparison

Adverse event rates (most common):

| Event | Semaglutide | Liraglutide | |-------|-------------|-------------| | Nausea | 44.2% | 38.6% | | Diarrhea | 30.2% | 20.5% | | Constipation | 22.5% | 18.9% | | Vomiting | 24.0% | 14.2% |

Semaglutide had numerically higher rates of nausea and vomiting, yet fewer patients discontinued due to adverse events (3.2% vs 12.6%). This paradox likely reflects the slower titration schedule allowing symptom adaptation, and the weekly dosing reducing peak-related symptoms versus daily liraglutide injections that produce daily Cmax fluctuations.

Limitations Acknowledged by the Investigators

The authors identified several constraints worth noting. The trial was open-label for the active comparators (semaglutide vs liraglutide), though double-blinded against placebo. Open-label design introduces potential bias in self-reported outcomes and adherence behavior. Participants knew which GLP-1 they received, which could affect diet/exercise motivation.

The population was 78% female and 83% White, limiting generalizability. Mean baseline BMI was approximately 37 kg/m², placing participants in the moderate-to-severe obesity range. Whether the 2.5:1 efficacy ratio holds at lower BMIs or in male-predominant cohorts remains unconfirmed.

The 68-week duration, while substantial, cannot confirm durability beyond that window. Given semaglutide's non-plateau trajectory, longer-term comparative data would strengthen clinical decision-making. No cardiovascular outcomes or hard clinical endpoints were assessed; the trial was powered for weight change only.

Clinical Translation

For prescribers choosing between these two FDA-approved GLP-1 agents for chronic weight management, STEP-8 provides the only direct randomized comparison. The data support semaglutide 2.4 mg as the more effective option across all categorical thresholds, with better adherence despite higher peak GI symptom rates. The weekly injection convenience and longer titration appear to offset the transient GI burden.

Cost and access remain separate considerations. At the time of publication, both agents carried similar list prices, but formulary placement and insurance coverage vary. The 2022 AGA guideline on pharmacological interventions for obesity references STEP-8 when recommending semaglutide as first-line pharmacotherapy for patients with BMI ≥30.

Frequently asked questions

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References

Rubino DM, Greenway FL, Khalid U, et al. Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: the STEP 8 randomized clinical trial. JAMA. 2022;327(2):138-150. https://pubmed.ncbi.nlm.nih.gov/35015037/
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. https://pubmed.ncbi.nlm.nih.gov/33567185/
FDA. Wegovy (semaglutide) prescribing information. 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf
FDA. Saxenda (liraglutide) prescribing information. 2014. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206321Orig1s000lbl.pdf
Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). N Engl J Med. 2023;389(24):2221-2232. https://pubmed.ncbi.nlm.nih.gov/37952131/
Garvey WT, Batterham RL, Bhatta M, et al. Two-year effects of semaglutide in adults with overweight or obesity (STEP 5). Nat Med. 2022;28(10):2083-2091. https://pubmed.ncbi.nlm.nih.gov/35441470/