STEP 8: semaglutide against liraglutide, head to head

Semaglutide and liraglutide are both GLP-1 drugs approved for weight management, and for years they were compared only across separate trials. STEP 8 put them in one study. At 68 weeks, average body weight was down 15.8% on weekly semaglutide 2.4 mg and 6.4% on daily liraglutide 3.0 mg [1].

Why this study matters

The two drugs share a target but differ in structure. The authors note that liraglutide has a half-life of 13 to 15 hours and semaglutide about 165 hours, which is why one is injected daily and the other weekly [1]. Separate trials suggested semaglutide produced more weight loss, but different populations make that a rough guide. STEP 8 is the direct comparison. Our breakdown of STEP 1 covers semaglutide against placebo, and the semaglutide evidence guide gives the wider record.

What they did

Adults were eligible with a body mass index of 30 or more, or 27 or more with at least one weight-related condition. They also needed at least one self-reported unsuccessful diet attempt. People with diabetes were excluded [1].

Of 338 people randomised, 126 received semaglutide, 127 liraglutide and 85 pooled placebo. In total, 319 (94.4%) completed the trial and 271 (80.2%) completed treatment. Both groups received counselling every 4 to 6 weeks on a 500 kcal daily deficit and at least 150 minutes of activity a week [1].

The semaglutide dose was raised over 16 weeks. The liraglutide dose was raised over 4 weeks, as its label sets out. Because the two schedules differ, the comparison between active drugs could not be masked. Each active group was blinded against its own matched placebo [1].

What they found

The headline gap was 9.4 percentage points (95% CI −12.0 to −6.8), or 8.5 kg. Against placebo, semaglutide lost 13.9 points more and liraglutide 4.5 points more [1]. For reference, STEP 1 reported 14.9% on semaglutide 2.4 mg against 2.4% on placebo at the same 68-week point, so the semaglutide result here is in line with that earlier trial [2].

The threshold percentages are among the 117 people per active arm with a week 68 measurement. The 5% figure was exploratory and not tested statistically. The odds of reaching 10% loss were 6.3 times higher on semaglutide than on liraglutide [1].

Semaglutide also did better than liraglutide on total cholesterol, triglycerides, HbA1c, fasting glucose and C-reactive protein, and on diastolic blood pressure at week 68. These were supportive endpoints and were not adjusted for multiple comparisons [1].

Safety reported

There were no deaths. Severe gastrointestinal events were uncommon, at 3.2%, 2.4% and 3.5% respectively, and most gastrointestinal events were mild to moderate and transient. One person on liraglutide had acute pancreatitis; none did on semaglutide or placebo [1]. The authors also report more insomnia on liraglutide and note that, when assessed prospectively, liraglutide has not been linked to more depression or suicidality [1].

Caveats

• Sponsor. Novo Nordisk funded the trial, and its representatives took part in design, conduct, analysis and the manuscript [1].
• Open label. The head-to-head comparison was unmasked. Matched placebo groups were the authors' mitigation [1].
• Unequal handling of poor tolerance. People who could not tolerate semaglutide 2.4 mg could drop to 1.7 mg. People who could not tolerate liraglutide 3.0 mg had to stop and restart. The authors say this may have raised liraglutide discontinuation and lowered its measured benefit [1].
• Discontinuation. Permanent discontinuation for any reason was 13.5% on semaglutide and 27.6% on liraglutide. In earlier trials the gap went the other way, so the authors treat the result with care [1].
• Who was in it. Most participants were women and 73.7% were white, all at US sites [1].
• Length. 68 weeks says nothing about longer outcomes, and the trial was not built to show effects on heart disease or other clinical events [1].
• Missing data. COVID-19 caused some telephone visits and missed measurements, but 92% of each group had a week 68 weight [1].

What it means in practice

The result is a comparison of two products used as labelled, not a recommendation of either. Choosing between them, or any medicine, depends on tolerance, cost, access and personal history, and belongs with a prescriber. The trial shows average differences. Individual responses varied in both arms, and the authors themselves stress that individual tolerance and sensitivity matter [1].

What is still open

• Whether the gap holds beyond 68 weeks, and after treatment stops.
• How results look under a fully blinded design or a crossover design.
• How the discontinuation pattern would change if both drugs handled poor tolerance the same way.
• How other, newer drugs compare. Our SURMOUNT-5 breakdown covers a different head-to-head.

What this means

We read STEP 8 as showing that, in a US trial of adults without diabetes who had regular counselling, weekly semaglutide 2.4 mg produced roughly two and a half times the average weight loss of daily liraglutide 3.0 mg, with similar overall side-effect rates [1]. The manufacturer of semaglutide ran the trial, and the rules for poor tolerance may have favoured semaglutide persistence. To argue the gap is mostly an artefact you would need a trial where both drugs are handled identically, and the sensitivity analyses in this one did not reverse the result.

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