What STEP-8 Actually Changes in Clinical Practice

At a glance

• N: 338 adults with obesity or overweight plus at least one weight-related comorbidity
• Intervention: Subcutaneous semaglutide 2.4 mg once weekly
• Comparator: Subcutaneous liraglutide 3.0 mg once daily
• Duration: 68 weeks (16-week dose-escalation, 52-week maintenance)
• Primary endpoint: Percentage change in body weight from baseline at week 68
• Key result: Semaglutide group lost 15.8% of body weight vs 6.4% for liraglutide (Rubino et al., JAMA 2022)

Why a Head-to-Head Trial Mattered

Before STEP-8, clinicians choosing between semaglutide and liraglutide for obesity relied on cross-trial comparisons. The STEP 1 program showed semaglutide 2.4 mg producing ~15% weight loss at 68 weeks. The SCALE program showed liraglutide 3.0 mg producing ~8% at 56 weeks. But differences in patient populations, run-in periods, and background lifestyle interventions made direct comparison unreliable. STEP-8 was designed specifically to eliminate that ambiguity by randomizing both drugs within the same protocol, same sites, and same follow-up window.

The trial also included open-label and double-blind treatment arms. Participants were randomized 3:1:3:1 to semaglutide (open-label), semaglutide (blinded), liraglutide (open-label), or liraglutide (blinded). This dual-design let investigators assess whether awareness of treatment assignment inflated weight-loss differences. It did not. The blinded arms showed a nearly identical separation.

Methodology Notes That Matter for Practice

Several design features deserve attention from prescribers applying these results to real patients.

Dose escalation mirrored FDA labels. Semaglutide was titrated from 0.25 mg weekly over 16 weeks to the target 2.4 mg dose, matching the Wegovy prescribing information. Liraglutide was titrated from 0.6 mg daily over 4 weeks to 3.0 mg, per the Saxenda label. This means the efficacy gap appeared even when both agents were dosed exactly as approved.

Lifestyle intervention was standardized. All participants received counseling targeting a 500 kcal/day deficit and 150 minutes/week of physical activity. Neither group had a pharmacological or behavioral advantage beyond the assigned drug.

BMI entry threshold was 30 kg/m² (or 27 with comorbidity). Mean baseline BMI was approximately 37.5 kg/m² across arms. Patients at the lower end of the BMI spectrum were underrepresented, which limits confidence in extrapolating the magnitude of difference to patients closer to the 27 kg/m² cutoff.

Excluded populations. The trial excluded patients with type 2 diabetes, prior bariatric surgery, and those using other weight-loss medications. Clinicians treating these groups cannot assume the same 2.5:1 efficacy ratio holds.

Results Beyond the Headline Number

The primary result (15.8% vs 6.4% weight loss) is widely cited. The secondary and exploratory endpoints tell a richer story.

Weight-Loss Thresholds Achieved

| Threshold | Semaglutide 2.4 mg | Liraglutide 3.0 mg | |---|---|---| | ≥5% body weight loss | 87.2% | 58.1% | | ≥10% body weight loss | 70.9% | 25.6% | | ≥15% body weight loss | 50.5% | 7.0% | | ≥20% body weight loss | 24.8% | 1.6% |

Source: Rubino et al., JAMA 2022, Table 2

The 10% threshold matters clinically because it is the point at which improvements in obstructive sleep apnea severity, NAFLD histology, and cardiovascular risk factors become more reliably observed. Over 70% of semaglutide patients crossed that line. Only one in four liraglutide patients did.

The 20% threshold is where outcomes begin to approximate surgical results for metabolic comorbidities. One in four semaglutide patients reached it. Virtually no liraglutide patients did.

Cardiometabolic Markers

Semaglutide showed greater reductions in waist circumference (−13.5 cm vs −6.8 cm), systolic blood pressure, and C-reactive protein. Lipid panel changes favored semaglutide for triglycerides and VLDL cholesterol but were comparable between groups for LDL. HbA1c reductions were modest in both arms, consistent with the non-diabetic study population.

Tolerability and Discontinuation

Gastrointestinal adverse events were the most common reason for treatment discontinuation in both arms. Nausea affected 44% of semaglutide patients vs 38% of liraglutide patients. Diarrhea rates were similar (~12% in both groups). However, the discontinuation rate due to adverse events was lower in the semaglutide arm (3.2%) than the liraglutide arm (12.6%).

This finding deserves emphasis. Despite comparable nausea rates, semaglutide patients were less likely to stop treatment. The once-weekly dosing schedule may contribute: patients experiencing transient post-injection nausea have six recovery days before their next dose, while daily liraglutide users face the prospect of symptoms every morning.

What Changed in Guidelines After STEP-8

American Gastroenterological Association (AGA), 2022

The AGA's clinical practice guideline on pharmacological interventions for adults with obesity, published in Gastroenterology, recommended semaglutide 2.4 mg as a first-line pharmacotherapy option. Liraglutide 3.0 mg was listed as an alternative. The guideline panel cited STEP-8 specifically as evidence supporting semaglutide's superiority within the GLP-1 receptor agonist class (Grunvald et al., Gastroenterology 2022).

Endocrine Society, 2024 Update

The Endocrine Society's updated clinical practice guideline placed semaglutide 2.4 mg and tirzepatide as preferred pharmacotherapy for obesity in adults. Liraglutide 3.0 mg was positioned lower in the treatment algorithm, appropriate mainly when weekly injectables are contraindicated or unavailable.

European Association for the Study of Obesity (EASO)

EASO's framework for obesity management similarly incorporated the STEP-8 data into its staging system. For patients at EASO Stage 2 or higher, the recommendation shifted toward semaglutide over liraglutide when both are accessible.

Which Prescribing Patterns Actually Shifted

STEP-8's publication coincided with severe semaglutide supply shortages in 2022-2023. This created a gap between guideline recommendations and real-world prescribing. During the shortage period, liraglutide prescriptions for obesity management increased, partly because it was what pharmacies could stock.

As supply stabilized through 2024, IQVIA data showed a clear trend: new liraglutide starts for obesity fell by roughly 40% year-over-year, while semaglutide 2.4 mg prescriptions grew. The clinical community had absorbed the STEP-8 message. When given a choice, prescribers picked the drug with 2.5x the weight loss and a lower discontinuation rate.

Three scenarios where liraglutide retained a role:

1. Patients who cannot tolerate semaglutide dose escalation. Some patients develop persistent nausea or vomiting at the 1.7 mg or 2.4 mg semaglutide doses. Switching to liraglutide (which acts on the same receptor but clears faster due to its shorter half-life) can be a reasonable step-down.

2. Insurance or cost constraints. In markets where semaglutide faces formulary restrictions, liraglutide may be the only covered GLP-1 RA for obesity.

3. Pediatric populations. Liraglutide 3.0 mg received FDA approval for adolescents aged 12+ with obesity before semaglutide did for this age group. Prescribers in pediatric obesity clinics continued using liraglutide based on its established safety data in younger patients.

What STEP-8 Does Not Tell You

Acknowledging what the trial cannot answer is as important as citing what it proved.

No cardiovascular outcomes data. STEP-8 was a 68-week weight-loss efficacy trial, not a MACE endpoint trial. The SELECT trial (semaglutide, published 2023) later demonstrated cardiovascular risk reduction, but that was at a different dose and in a different population. Clinicians should not cite STEP-8 when counseling patients about heart attack or stroke prevention.

No data on weight regain after discontinuation. The STEP 1 extension study showed significant weight regain after semaglutide cessation. STEP-8 did not include a post-treatment observation period. Whether the larger initial weight loss with semaglutide translates into better long-term maintenance after drug withdrawal remains unknown.

Limited ethnic and racial diversity. The trial enrolled participants primarily from the United States and was ~75% White. GLP-1 receptor agonist pharmacokinetics do not differ meaningfully by race, but baseline body composition and comorbidity profiles do. The absolute weight-loss numbers may differ in populations not well represented in the trial.

No comparison to tirzepatide. By the time STEP-8 was published, the SURMOUNT program had reported even larger weight losses with tirzepatide (a dual GIP/GLP-1 RA). STEP-8 established semaglutide's dominance over liraglutide but said nothing about where semaglutide stands relative to newer dual-agonist therapies.

A Practical Decision Framework for Clinicians

The following framework synthesizes STEP-8 results with post-trial evidence and current access realities.

Start with semaglutide 2.4 mg when:

• The patient has a BMI ≥30 (or ≥27 with comorbidity) and no contraindications to GLP-1 RAs
• Insurance covers semaglutide, or cost is not prohibitive
• The patient can commit to weekly self-injection

Consider liraglutide 3.0 mg when:

• Semaglutide is not tolerated at therapeutic doses
• Semaglutide is not accessible due to formulary or supply issues
• The patient is an adolescent (12-17) in a setting where semaglutide lacks age-specific approval

Reassess at 16 weeks. Both FDA labels recommend evaluating response at the end of dose titration. If a patient on liraglutide has not achieved ≥4% weight loss by week 16, the STEP-8 data argue strongly against continuing liraglutide in hopes of a late response. Switching to semaglutide (or escalating to tirzepatide) becomes the evidence-based move.

Frequently asked questions

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References

1. 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. PubMed
2. Grunvald E, Shah R, Hernaez R, et al. AGA clinical practice guideline on pharmacological interventions for adults with obesity. Gastroenterology. 2022;163(5):1198-1225. PubMed
3. Wegovy (semaglutide) prescribing information. Novo Nordisk. FDA Label
4. Saxenda (liraglutide) prescribing information. Novo Nordisk. FDA Label
5. 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
6. 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. PubMed