What Tripling the Dose Buys

A higher dose of semaglutide — 7.2 mg against the approved 2.4 mg — was tested head to head in 1,407 people over 72 weeks. It produced 18.7% weight loss against 15.6%.^[1] Three extra percentage points is the benefit. The costs are in the safety table, and one of them is a side effect that barely exists at the standard dose.

What the trial did

Adults with a BMI of 30 or above and without diabetes were randomized five-to-one-to-one across 95 centers in 11 countries: 1,005 to semaglutide 7.2 mg, 201 to 2.4 mg, and 201 to placebo, for 72 weeks. Participants averaged 47 years old, 113 kg, and a BMI of 39.9, and 73.7% were women.

The lopsided allocation is deliberate. The question is what the new dose does, so most participants go there; the comparison arms only need to be large enough to anchor it.

Against the standard dose, the higher one gave an estimated 3.1 percentage points more weight loss (95% CI −4.7 to −1.6) and made people roughly twice as likely to reach a 25% reduction (odds ratio 2.4). Waist circumference fell 11.7 cm more than placebo.

The side effect that is new at this dose

Gastrointestinal effects also rose — 70.8% against 61.2% — but those are familiar, expected, and mostly fade. An unfamiliar sensory effect appearing in a quarter of people at a higher dose is a different kind of information, and it deserves to be named rather than folded into a total.

Three more percentage points of weight loss, and seventeen more of altered sensation.

The trial’s own interpretation is that the higher dose retained a favorable risk-benefit profile. That may well be right for someone who has not reached their goal at 2.4 mg and for whom the extra loss matters. It is a judgment rather than a measurement, and a reader given both columns can make their own.

The row that goes the other way

Serious adverse events were lower at 7.2 mg — 6.8% against 10.9% at 2.4 mg. Reported alone, that reads as the higher dose being safer, which is almost certainly wrong.

The 2.4 mg arm contained 201 people against 1,005 at the higher dose. In a group that size, a handful of unrelated events shifts the percentage by whole points, and 10.9% versus 6.8% is within what chance produces. Including this row matters because omitting inconvenient numbers is precisely the practice this register documents in sellers, and the discipline applies to results that favor a drug as much as to ones that do not.

Reading the 2.4 mg column

That is the value of an active-controlled design. Most trials answer “is this better than nothing.” This one answers “is this better than what you would otherwise be prescribed,” which is the question a patient actually faces.

Two closing notes: the trial was funded by Novo Nordisk, which makes semaglutide, and for what the higher dose costs in dollars rather than side effects see what 7.2 mg costs.