Percentage of loss, absolute kilograms, and the sleight of hand between them

What the substudies found is not in serious dispute. In both programmes, the proportion of body mass that was fat fell and the proportion that was lean rose, which is the arithmetic signature of losing more fat than lean tissue. In both, the absolute quantity of lean mass also fell, because a person shedding a fifth of their body weight sheds some of everything. Whether that second fact matters is where the evidence stops and the interpretation starts, and the interpretation has been conducted at a volume wholly disproportionate to the underlying data.

Bioimpedance measures conductivity and calculates everything else

Bioelectrical impedance analysis passes a small alternating current through the body and measures the opposition to it. Lean tissue, being largely water and electrolyte, conducts; fat does not. From the measured impedance, a height term, a weight term and a set of population-derived regression equations, the device produces a fat mass figure. The impedance is measured. The body composition is computed from an equation fitted to somebody else.

The consequences are well documented. Agreement with DXA at the group level is often reasonable; agreement at the individual level is not, with limits of agreement for fat mass frequently spanning several kilograms in either direction, and the disagreement growing at higher body mass index — precisely the population of interest here.¹ Worse for our purposes, the measurement is sensitive to hydration status, recent exercise, recent meals, ambient temperature, skin moisture and time of day, all of which are changing during incretin treatment. A device that reads fat mass as a function of body water, used in a person whose body water is unstable, will report composition changes that are hydration changes. The Journal does not report BIA-derived composition changes from consumer devices, and would not treat them as evidence of anything.

The method that measures muscle directly, and why nobody uses it

There is a technique that estimates whole-body skeletal muscle mass rather than inferring it from a subtraction. Deuterated creatine dilution involves an oral dose of labelled creatine, which distributes into the total creatine pool — almost all of which sits in skeletal muscle — with the enrichment of labelled creatinine in a subsequent urine sample giving an estimate of pool size and therefore of muscle mass.² It is not an imaging measure and it does not depend on regression equations fitted to a reference population.

Comparisons with DXA are instructive and slightly deflating. The two methods correlate only moderately in older adults, and where they disagree the creatine-dilution figure has been the better predictor of physical function and of incident disability. That is an argument that DXA appendicular lean mass, the standard proxy, is measuring something adjacent to what matters rather than the thing itself.

The method has been available for more than a decade. It has been used in no trial of any drug in this class. It requires a timed urine collection and a mass spectrometry laboratory, which is a modest imposition set against the volume of argument the absence of good muscle-mass data has generated.

What the semaglutide DXA substudy measured

In the STEP 1 trial of once-weekly semaglutide 2.4 mg in adults with overweight or obesity without diabetes, mean weight reduction at sixty-eight weeks was approximately 14.9 per cent against 2.4 per cent on placebo.³ A body-composition substudy conducted at a subset of sites scanned approximately one hundred and forty participants by dual-energy X-ray absorptiometry at baseline and at week sixty-eight.

The substudy reported a reduction in total fat mass of roughly nineteen per cent in the semaglutide group, a smaller absolute reduction in lean body mass, and consequently an increase in the proportion of total body mass that was lean — from approximately fifty-seven per cent at baseline to approximately sixty-one per cent at week sixty-eight. Regional visceral fat mass fell proportionally more than total fat mass, which is the metabolically favourable direction.

Converted into the currency people argue in, roughly a third to two-fifths of the total mass lost in that substudy was lean tissue by the DXA definition. That is unremarkable against the dietary weight-loss literature. It is also a group mean from one hundred and forty people, reported at a single follow-up point, with no strength or function measurement alongside it.

The tirzepatide substudy, and the ratio it reported

SURMOUNT-1 randomised adults with obesity or overweight without diabetes to tirzepatide at 5, 10 or 15 mg weekly or placebo for seventy-two weeks, with mean weight reduction of approximately 20.9 per cent at the highest dose against 3.1 per cent on placebo.⁴ A DXA substudy of approximately one hundred and sixty participants measured composition at baseline and at week seventy-two.

The reported result is usually summarised as a three-to-one ratio: total fat mass fell by roughly a third while lean mass fell by roughly a tenth, so approximately three-quarters of the mass lost was fat. The substudy also reported that the ratio of fat mass to lean mass change was more favourable on tirzepatide than on placebo, which is the comparison that matters and the one most often omitted, because placebo participants who lost a small amount of weight lost a proportionally larger share of it as lean tissue.

The Journal notes two limits on this figure. It is a mean across three dose arms pooled in some analyses and reported separately in others, and secondary coverage rarely says which. And a favourable ratio applied to a very large total loss still yields a substantial absolute lean-mass reduction, which is the legitimate residue of the concern.

The magnetic-resonance substudy in the diabetes programme

The most methodologically interesting composition data in this class did not come from an obesity trial. A magnetic-resonance imaging substudy within SURPASS-3, comparing tirzepatide against insulin degludec in type 2 diabetes, measured liver fat content and abdominal adipose tissue volumes rather than whole-body compartments.⁵ Approximately three hundred participants were imaged, which makes it the largest imaging substudy in the programme.

Liver fat content fell substantially more on tirzepatide than on insulin, as did visceral adipose tissue volume, and the separation between the arms was larger than the difference in total body weight would predict. That is the single most useful composition finding in the class, because it shows the two interventions redistributing tissue differently rather than merely producing different amounts of weight change.

Magnetic resonance is the better instrument for this question by some distance: it measures adipose tissue volumes directly and separates visceral from subcutaneous depots, neither of which DXA does well. It is also expensive, slow and unavailable at most trial sites, which is why the whole-body composition argument is still being conducted on DXA data from a few hundred people.

What the substudies were never powered to detect

An imaging substudy inside a large trial is sized to describe rather than to test. The enrolment is set by how many participating sites have a scanner and by what the sponsor budgeted, not by a power calculation against a composition hypothesis, and the analysis is generally pre-specified as exploratory or descriptive. The consequence is that these substudies can report a mean change with a usable confidence interval and cannot support most of the questions asked of them.

They cannot, for instance, establish whether lean-mass change differs between dose arms, because the per-arm enrolment after splitting is in the low tens. They cannot establish whether it differs by age, sex, baseline adiposity or diabetes status, because those subgroups were not enrolled to be comparable. They cannot describe the distribution of individual responses, because the per-participant least significant change is a substantial fraction of the observed mean effect. And they cannot address function at all, because nobody measured it.

Nor was the imaging repeated when the programmes were extended. The two-year semaglutide extension reported weight, waist circumference and cardiometabolic parameters at week 104 and did not repeat the composition substudy, so there is no imaging at all beyond seventy-two weeks in this class.⁶ Whatever the trajectory of lean mass is in year two of treatment, nobody has measured it.

None of this is a scandal; it is the ordinary economics of trial substudies. It becomes a problem only when a descriptive group mean is quoted as though it characterised what will happen to an individual, which is now the normal register of coverage on this subject.

The endpoint nobody measured

The clinical question is not how many kilograms of lean tissue a person has. It is whether they can climb stairs, rise from a chair without using their arms, carry shopping, and recover from an illness that keeps them in bed for a week. Those are measurable — grip strength, gait speed, chair-stand time, stair-climb power, the short physical performance battery — and they are measured routinely in geriatrics and sports science. Not one phase 3 trial in this drug class has reported them as a pre-specified endpoint.

That absence is the strongest available criticism of the programmes, and it has been made in the general medical literature by authors who are otherwise unsympathetic to muscle-loss alarmism.⁷ Their argument is worth stating precisely: the concern about lean-mass loss is plausible but unquantified, the instrument used to assess it is a poor proxy for the tissue of interest, and the endpoints that would settle whether it matters are cheap, validated and were simply not collected.

Where function has been measured during substantial weight loss by other routes, the results are mostly reassuring: physical performance usually improves, because carrying less mass is itself a functional benefit. That is a reasonable prior and it is not a substitute for the measurement.

On the phrase "muscle-sparing"

Two commercial claims have attached themselves to this subject and both deserve naming. The first is that a particular agent in the class is muscle-sparing relative to the others. No head-to-head trial has compared body composition between agents in this class, at matched weight loss or otherwise. Cross-trial comparison of DXA substudies with different populations, durations, scanners and analysis definitions cannot support a ranking, and every published ranking of that kind is an artefact of the comparison rather than a finding.

The second is that a supplement, peptide or co-administered compound preserves lean mass during incretin treatment. The Journal has reviewed the material behind several such claims and found the same structure each time: a mechanistic rationale, a small study in a different population or in animals, and no randomised evidence in anybody taking a GLP-1 receptor agonist. Several of the compounds marketed for this purpose are sold for research use only and are not approved for human use in any jurisdiction, a fact that the marketing generally states in small type and contradicts in large.

Neither claim is refuted. Both are unevidenced, which in a market this size is the more useful thing to establish.

How the Journal reports a body-composition figure

Four things accompany every composition number in these pages. The instrument, because DXA, magnetic resonance, bioimpedance and creatine dilution are not interchangeable and the choice frequently determines the sign of the result. The sample size of the substudy rather than of the parent trial, because the parent trial size is irrelevant to the composition finding and quoting it is misleading. The definition used — total lean mass, lean soft tissue, appendicular lean mass or fat-free mass — because these differ by several kilograms in the same person. And whether the figure is a proportion of body mass or an absolute quantity.

Where a source omits any of the four, we say so rather than guessing, and where we have had to convert between definitions we show the conversion. This is more cumbersome than the alternative and it is the only way we have found to write about this subject without producing sentences that are technically true and practically misleading.

Readers who find a figure in these pages that lacks its instrument and its sample size have found an error, and the standards desk would like to hear about it at standards@compoundjournal.com.

What the testing services can and cannot tell you here

A category confusion arrives in the Journal postbag with some regularity, and it is worth addressing directly. The four independent testing services this market relies on — Janoshik, Medutest, PeptideMeter and VendorInvestigate — analyse the contents of a vial. They report chromatographic purity, identity by mass, sometimes peptide content, and in the case of the verification services, what they were able to establish about a supplier. None of them measures anything about a person.

A certificate stating 98.7 per cent purity for a batch supplied by WWB, SSA or KP is silent on that customer’s body composition, and a low-purity result does not explain a disappointing DXA scan. The two questions are answered by different instruments in different buildings, and conflating them produces a particular kind of dead end in which somebody spends several hundred pounds on analytical testing to investigate a clinical question.

The reverse confusion also occurs: a satisfactory laboratory panel or a favourable body-composition scan is offered as evidence that a vial contained what its label claimed. It is not evidence of that either. Compounds sold for research use only are not approved for human use, and nothing in this section should be read as advice about using them.

The next instalment in this department takes up the question that follows this one chronologically rather than logically: what happens to all of it when treatment stops. The composition of regained weight is a separate literature, it is thinner than this one, and what little exists is not encouraging.