STEP 8 Trial: Semaglutide vs. Liraglutide Head-to-Head Results Explained

What Was the STEP 8 Trial?

STEP 8 was a 68-week, randomized, open-label, double-dummy controlled trial published in JAMA in January 2022. It enrolled 338 adults without type 2 diabetes and compared once-weekly subcutaneous semaglutide 2.4 mg to once-daily subcutaneous liraglutide 3.0 mg, both alongside a reduced-calorie diet and increased physical activity. This was the first head-to-head RCT of two approved GLP-1 receptor agonists specifically for weight management, and the size of the difference between arms surprised many clinicians.

Before STEP 8, the field lacked direct comparative data. Clinicians were choosing between semaglutide and liraglutide based on indirect comparisons across separate trials conducted under different protocols, in different populations, with different follow-up periods. Cross-trial comparisons are notoriously unreliable because baseline BMI, diet co-intervention intensity, and placebo response rates all vary. STEP 8 eliminated that problem by running both agents in the same protocol, at the same sites, over the same 68 weeks. [1]

The trial used a double-dummy design to maintain blinding: every participant injected both a weekly pen and a daily pen, one of which contained placebo. This is methodologically sound for an open-label comparison and reduces the performance bias that can inflate results for a more convenient dosing schedule.

STEP 8 Primary and Key Secondary Results

The primary endpoint was percentage change in body weight from baseline to week 68. Semaglutide delivered a 15.8% mean reduction versus 6.4% for liraglutide, a difference of 9.4 percentage points (P<0.001). [1]

The secondary outcomes tell an equally clear story. 75.3% of participants on semaglutide lost at least 10% of body weight compared with 27.0% on liraglutide. For the 20% threshold, 38.5% of the semaglutide group reached it versus only 2.8% of the liraglutide group. [1] Those are not small differences. The proportion achieving 20% weight loss was more than thirteen times higher on semaglutide.

Waist circumference fell by 13.5 cm on semaglutide versus 7.4 cm on liraglutide. Systolic blood pressure, LDL cholesterol, and fasting glucose all improved more in the semaglutide arm, though the trial was not powered for cardiovascular outcomes.

On tolerability, the discontinuation rate due to adverse events was lower for semaglutide (3.5%) than for liraglutide (7.8%), despite gastrointestinal side effects being the predominant complaint in both groups. The daily injection burden of liraglutide likely contributed to its higher dropout rate, though the trial design cannot formally separate injection-site fatigue from pharmacological tolerability.

How STEP 1 Established the Benchmark

STEP 1 was the key registration trial for Wegovy in adults without diabetes. Published in the New England Journal of Medicine in March 2021, it enrolled 1,961 adults with a BMI ≥30 or ≥27 with at least one weight-related comorbidity. [2]

Mean body-weight reduction at 68 weeks was 14.9% for semaglutide versus 2.4% for placebo. 86.4% of the semaglutide group lost at least 5% of body weight, and 69.1% lost at least 10%. The NEJM paper noted: "The mean change in body weight was -14.9 percentage points with semaglutide vs. -2.4 percentage points with placebo." Those absolute numbers became the standard against which every subsequent obesity drug gets measured. [2]

STEP 1 also documented meaningful improvements in cardiometabolic risk factors. Waist circumference fell 13.54 cm, systolic blood pressure dropped 6.16 mmHg, and HbA1c decreased 0.38 percentage points despite participants not having diabetes. The trial ran 68 weeks, identical to STEP 8, which is why comparing the two is more defensible than most cross-trial analyses.

One limitation STEP 1 acknowledged: weight loss plateaued around week 60 to 64, suggesting that 68 weeks may not capture the full pharmacological effect. STEP 5 addressed exactly that question.

STEP 2: Semaglutide in People With Type 2 Diabetes

STEP 2, published in The Lancet in March 2021, enrolled 1,210 adults with type 2 diabetes and a BMI ≥27. [3] The presence of T2D substantially attenuates GLP-1-driven weight loss, a pattern seen consistently across the GLP-1 class.

Mean weight loss at 68 weeks was 9.6% with semaglutide 2.4 mg, 7.0% with semaglutide 1.0 mg (the diabetes dose), and 3.4% with placebo. HbA1c fell 1.6 percentage points in the 2.4 mg arm. [3] Even blunted by the metabolic context of T2D, semaglutide 2.4 mg still outperformed the 1.0 mg dose approved for glycemic control alone, which justified pursuing full approval of the higher dose in this population.

For clinicians prescribing in the real world, STEP 2 data clarifies expectations: patients with T2D should be counseled that their weight loss trajectory will likely land closer to 9 to 10% rather than the 15% seen in metabolically healthier populations.

STEP 3: Adding Intensive Behavioral Therapy

STEP 3, published in JAMA in April 2021, tested whether layering intensive behavioral therapy onto semaglutide 2.4 mg could push results beyond STEP 1 levels. [4] The trial enrolled 611 adults without T2D. The semaglutide-plus-intensive-behavioral-therapy group lost 16.0% of body weight versus 5.7% in the placebo-plus-intensive-behavioral-therapy group. [4]

The headline result looks similar to STEP 1, which can be interpreted two ways. First, intensive behavioral therapy adds roughly 1 percentage point of incremental benefit when semaglutide is already present. Second, the behavioral intervention alone (placebo arm) produced meaningful weight loss, confirming that structured lifestyle support is not inert. The JAMA authors noted that intensive behavioral therapy in the placebo group produced "a clinically meaningful response," which suggests that patients who decline pharmacotherapy still benefit from intensive program enrollment.

From a clinical decision-making standpoint, STEP 3 supports combining structured behavioral programs with semaglutide for patients who have access to them, but shows that most of the pharmacological effect exists independent of that combination.

STEP 5: Two-Year Data Changes the Durability Picture

STEP 5 extended follow-up to 104 weeks in 304 adults without T2D, making it the longest dedicated semaglutide weight-loss RCT at the time of publication. Published in Nature Medicine in October 2022, it found that mean body-weight reduction reached 15.2% at 104 weeks for semaglutide versus 2.6% for placebo. [5]

The weight-loss curve continued to decline from week 68 through approximately week 84, then plateaued, which tells us that some patients have not reached their maximum pharmacological response at the 68-week endpoint used in STEP 1 and STEP 8. 77.1% of participants on semaglutide lost at least 10% by two years. [5]

Cardiometabolic improvements tracked alongside weight loss. Systolic blood pressure was reduced by 8.7 mmHg, waist circumference by 14.8 cm, and fasting plasma glucose by 0.4 mmol/L. STEP 5 also captured what happens when a plateau sets in: weight regain does not appear spontaneously during continued treatment, which argues against the concern that the drug "stops working" at some arbitrary point.

The two-year data also provided safety context. Gastrointestinal events were most common during the dose-escalation phase (weeks 1 to 20) and declined substantially once patients reached maintenance dosing at 2.4 mg. Serious adverse events occurred in 9.7% of the semaglutide group versus 5.8% placebo, though the trial was not powered to detect differences in specific serious event categories. [5]

Contextualizing the STEP Program Against SURMOUNT and SELECT

The STEP trials cover semaglutide 2.4 mg comprehensively, but the competitive context for treatment decisions now includes tirzepatide (Zepbound) and cardiovascular outcome data.

SURMOUNT-1, published in the NEJM in 2022, showed tirzepatide 15 mg produced 20.9% mean weight loss at 72 weeks in adults without T2D (N=2,539). [6] That surpasses STEP 1 results for the highest tirzepatide dose, though the trials differ in duration, population, and design. SURMOUNT-2 (Lancet 2023, N=938) showed tirzepatide 15 mg produced 15.7% weight loss in T2D patients, compared with the 9.6% seen in STEP 2. [7]

SELECT, published in the NEJM in November 2023 (N=17,604), added a different dimension entirely. Semaglutide 2.4 mg reduced major adverse cardiovascular events by 20% in adults with established cardiovascular disease and overweight or obesity but without diabetes, over a mean follow-up of 39.8 months. [8] SELECT did not study liraglutide. No MACE trial of comparable size exists for liraglutide at the 3.0 mg obesity dose.

For patients with established cardiovascular disease who also need weight management, SELECT positions semaglutide as the evidence-supported choice in the absence of comparable tirzepatide cardiovascular outcome data.

The STEP 8 Dosing and Titration Protocol

Understanding the titration schedule matters for both efficacy and tolerability. Both agents in STEP 8 used standard escalation:

Semaglutide started at 0.25 mg weekly for four weeks, then 0.5 mg for four weeks, 1.0 mg for four weeks, 1.7 mg for four weeks, then 2.4 mg maintenance. The FDA-approved Wegovy titration matches this schedule exactly. [9]

Liraglutide started at 0.6 mg daily for one week, then 1.2 mg for one week, 1.8 mg for one week, 2.4 mg for one week, then 3.0 mg maintenance. Reaching full dose takes five weeks versus twenty weeks for semaglutide. That faster escalation may partially explain the higher early discontinuation rate on liraglutide: patients encounter peak GI side effects sooner, before any tolerance develops.

A clinician prescribing semaglutide must counsel patients that weeks 1 to 20 are the highest-risk period for nausea and vomiting, and that the side effect burden typically decreases substantially after reaching 2.4 mg. The STEP 8 data showing lower discontinuation for semaglutide despite similar GI event rates confirms that the slower titration translates to better adherence.

Who Benefits Most: Patient Selection Considerations

The STEP trial program collectively informs a practical selection framework for clinicians choosing between agents.

Patients without T2D and without established cardiovascular disease who want maximum weight loss: STEP 1, STEP 3, and STEP 5 data support semaglutide 2.4 mg as first-line, with 14.9 to 16.0% mean weight loss expected. Where tirzepatide is accessible and affordable, SURMOUNT-1 data supports higher expectations at the 15 mg dose.

Patients with T2D needing weight loss: STEP 2 shows 9.6% with semaglutide 2.4 mg. SURMOUNT-2 shows 15.7% with tirzepatide 15 mg, a meaningful difference in a population where weight loss is harder to achieve. The Zepbound FDA label (2024) covers BMI ≥27 with a weight-related comorbidity, so T2D qualifies. [10]

Patients with established cardiovascular disease: SELECT data provides a specific 20% MACE risk reduction rationale for semaglutide that no competing agent can currently match with equivalent evidence. [8] The American Heart Association's 2023 science advisory on GLP-1 agents in cardiovascular disease reinforces this position.

Patients who tried liraglutide and achieved insufficient weight loss: STEP 8 shows that switching to semaglutide is not simply swapping two equivalent drugs. The 9.4-percentage-point difference in mean weight loss represents a clinically distinct treatment for a large proportion of patients.

Patients with prior GI intolerability on liraglutide: The lower STEP 8 discontinuation rate on semaglutide (3.5% vs. 7.8%) suggests that GI-related failure on liraglutide is not a reliable predictor of failure on semaglutide. The slower titration of semaglutide changes the tolerability profile substantially.

The AACE/ACE obesity clinical practice guidelines specify that pharmacotherapy should be considered when BMI is ≥30, or ≥27 with at least one obesity-related comorbidity, and lifestyle modification alone has been insufficient. [11] Both semaglutide and liraglutide meet that bar; the STEP 8 data determines which one to reach for first.

Practical Prescribing Notes From the STEP Data Collectively

Adherence to injection technique affects tolerability. Subcutaneous injections in the abdomen, thigh, or upper arm should rotate sites weekly. Both the Wegovy and Saxenda auto-injector pens are pre-filled; neither requires manual dose drawing.

Contraindications shared by both agents include personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. The Wegovy FDA label (2024 update) lists these prominently and includes a black-box warning. [9]

Drug interactions are modest but real. Both agents slow gastric emptying, which can reduce peak plasma concentration of oral medications taken with food. Patients on oral contraceptives, thyroid replacement, or time-sensitive anticoagulants may need timing adjustments.

Stopping either drug results in weight regain. SURMOUNT-4 (JAMA 2024, N=670) quantified this for tirzepatide: participants who discontinued after 36 weeks of treatment regained approximately 14 percentage points of body weight over the following 52 weeks, while those who continued lost another 5.5 percentage points. [12] A similarly designed withdrawal study for semaglutide (STEP-4, not covered in this article) showed comparable patterns of regain after discontinuation, which the FDA label reflects by describing semaglutide as a chronic treatment.

The STEP 8 finding that semaglutide produces roughly double the weight loss of liraglutide with better adherence gives clinicians and patients a data-grounded reason to start with the more effective agent rather than escalating after a liraglutide failure.