Grams per kilogram of what? The denominator problem in protein guidance

Ask where the number came from and the answer is usually a review article citing a review article. The Journal has traced the chain for the figures quoted most often in consumer material, and the terminus is generally one of three trials in resistance-trained young adults under moderate energy restriction. Those are good studies. They enrolled nobody over sixty, nobody with a body mass index above thirty-five, and nobody losing weight at the rate this drug class produces.

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.¹ 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.

Where the protein number comes from

The figures in circulation — commonly one and a half to two grams of protein per kilogram of body weight daily, sometimes expressed as a floor of around a hundred grams — are traceable. The most-cited primary source is a randomised trial in resistance-trained young men under a substantial energy deficit, comparing a higher against a lower protein intake with supervised training and controlled feeding; the higher-intake group gained lean mass and lost more fat over four weeks.² Supporting evidence comes from a large meta-analysis of protein supplementation during resistance training, which found a benefit to lean mass accrual that plateaued at around one and a half to one point six grams per kilogram daily.³

Both are good studies. Neither enrolled anybody over about thirty-five, anybody with obesity, or anybody losing weight at more than a small fraction of the rate this drug class produces. The plateau figure in particular is a plateau for training-induced accrual in weight-stable or mildly deficit conditions, and its application as a preservation target during a twenty per cent weight reduction is an extrapolation rather than a finding.

The Journal quotes these numbers because they are the best available and states their provenance because the provenance is the argument.

Grams per kilogram of what

A ratio requires a denominator and this one has at least three in common use. Per kilogram of current body weight, one and a half grams gives a hundred and eighty grams a day for a person weighing a hundred and twenty kilograms — an intake that is difficult on a normal appetite and close to unachievable on a suppressed one. Per kilogram of a reference or ideal body weight, the same ratio gives perhaps a hundred and five grams. Per kilogram of measured lean mass, higher ratios are conventional and the absolute target lands somewhere between the two.

Guidance in the obesity literature generally uses reference weight or an adjusted weight for precisely this reason, and consumer material generally uses current weight without saying so, which inflates the target by a third or more in the population most likely to be reading it. A person then fails to meet an inflated target and concludes they are losing muscle.

The Journal reports protein targets against an explicitly named denominator, every time, and regards a gram-per-kilogram figure without a stated denominator as uninformative. Where a source does not say which weight it means, that is worth noticing rather than resolving by assumption.

What the systematic reviews support

Two syntheses are worth separating. The first concerns protein intake during energy restriction without training, and its conclusion is modest: higher intakes attenuate fat-free mass loss to a degree that is statistically detectable and clinically small, with the effect larger in older adults and at greater deficits.⁴ The second concerns protein plus resistance training, where the effect is larger and more consistent, and where the protein and the training are difficult to separate because they interact.

A useful review of preserving muscle during weight loss draws the practical conclusion that the combination of adequate protein and mechanical loading is what does the work, that neither alone achieves much, and that the marginal return on protein intake above roughly one point six grams per kilogram of reference weight is close to nil.⁵ That last point is the one most often dropped: the dose-response curve flattens, and intakes of three grams per kilogram — which appear in consumer advice with some regularity — have no supporting evidence and a real opportunity cost in an appetite that only accommodates so much food.

None of these syntheses included a participant taking an incretin. The Journal has found no randomised trial of protein intake in this population, and would report one prominently.

What the older-adult trials found

The closest analogue to rapid weight loss in an older, heavier population predates this drug class entirely. In a randomised trial of adults aged sixty-five and over with obesity, assigned to diet, exercise, both or a control condition for a year, the combination produced the largest improvement in physical function, and the exercise component attenuated the loss of lean mass and of bone mineral density that diet alone caused.⁶ Diet alone improved function too — carrying less mass helps — but by less, and at a measurable skeletal cost.

That trial is the template for how the question should be asked in this class: randomise the co-intervention, measure function as a primary endpoint, measure bone, and follow for long enough for the skeleton to respond. Its population, older and heavier and losing weight quickly, resembles a large share of current incretin users far more closely than the young resistance-trained cohorts from which most consumer advice descends.

The Journal cites it frequently for that reason and notes the obvious limitation: the weight loss achieved was roughly a tenth of body mass over a year, which is half or less of what the current agents produce. Whether the protective effect of training holds at twice the rate of loss is not established.

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.

Two things follow practically and only two. Eating adequate protein and loading the skeleton during rapid weight loss are supported by general physiology, carry negligible risk, and are worth doing. Expecting either to prevent lean-mass loss outright is not supported by anything, and treating a fall in a DXA number as a failure of adherence is a misreading of what the number can tell you.