July 2024

The interventions with trial support, and the much longer list without

The intervention with the clearest evidence is the one nobody frames as an intervention: adjusting the dose.

Discontinuation rates, read honestly

An effect is dose-limiting when it prevents adequate intake, prevents normal activity, or produces a risk of its own. Discomfort…

What the tirzepatide schedule assumes about a person it has never met

We work the arithmetic out in full, because it is arithmetic and it is short.

Dose-limiting: a definition worth being strict about

Roughly four to seven per cent of trial participants discontinued for adverse events, mostly gastrointestinal, mostly during…

What actually helps, ranked by evidence

Almost nothing in the standard management repertoire has been tested in a randomised trial in this specific population. We say…

The mechanism behind the mechanism

The receptor populations that produce satiety and the ones that produce nausea overlap substantially. That is why the ceiling of…

Reading the dulaglutide titration schedule as a regulatory artefact

The published ladder exists because a protocol needed a single number. Practice has never followed it exactly, and the…

What a split-sample exercise can establish, and what it cannot

The Journal submitted split samples from single lots to three assay services, under names unconnected to this publication, and…

Retest date, expiry date, and the two conventions being confused

What happens to traceability when bulk material is subdivided, repackaged and relabelled two or three times before sale.

Who signed this, and what did they undertake by signing it

A manufacturer’s certificate is a self-declaration. An accredited laboratory’s report is a third-party measurement. The trade…

The batch number is the only thing connecting the page to the vial

What happens to traceability when bulk material is subdivided, repackaged and relabelled two or three times before sale.

What we asked twenty suppliers about stability data

We asked twenty companies three questions about stability data and print every answer, refusal and non-response.

The question no chromatogram has ever answered

Every certificate circulating in this market answers a question about molecules. Almost none answers a question about organisms,…

From vial to bench: what is recorded and what is assumed

What a laboratory can and cannot know about the provenance, storage history and representativeness of what lands on its bench.

Which results are findings and which are consequences of the weight loss

Three different explanations for the same abnormal number, and how to tell them apart.

A year after stopping: what the trials found at the far end

The physiology of regain was described a decade before these drugs, and it explains the trajectory without invoking anything…

Seasonal use, holiday use, and the honest state of the evidence

An absence of evidence is not evidence of harm. It is also not a licence.

Lean mass is a compartment, not a tissue

A body-composition report gives four decimal places and no confidence interval. That is the whole difficulty in one sentence.

Weight regain is not a failure of willpower and it is not a mystery

The variance around the mean regain trajectory is large and unexplained, exactly as it is for the weight loss.

Why people actually stop, in the order they actually stop

A supply interruption is a discontinuation with no notice, no taper and no plan. That is a distinct clinical situation.

Seasonal use, holiday use, and the honest state of the evidence

The vocabulary is borrowed, the rationale is usually mechanistic, and the outcome data does not exist.

Why people actually stop, in the order they actually stop

A supply interruption is a discontinuation with no notice, no taper and no plan. That is a distinct clinical situation.

Twenty-eight days is a number from somebody else’s product

We set out what is known, what is inferred and what is simply assumed about the fortnight after a vial is opened.

A named analyst is the cheapest quality signal in this trade

What the Journal asks when a document arrives unsigned, and what the answers have been.

Turnaround, cost and accreditation across the services this trade relies on

A compendial sterility test takes fourteen days of incubation and consumes the containers tested. That timescale is incompatible…

Pore size, particle size, and why peptides need the wide pores

A shallow gradient resolves impurities that a steep one runs into the parent peak. Both methods are legitimate; only one of them…

The fourteen-day problem, and what it does to a commercial testing model

Endotoxin is the more tractable of the two questions, and a kinetic chromogenic determination is neither slow nor exotic. It is…

From vial to bench: what is recorded and what is assumed

The condition on arrival is recorded by some services and not others, and it is one of the more informative lines in a report.

Check the vial, not the box

The interval between manufacture and analysis is the most under-read figure on the page, and the one most likely to matter by…

Benzyl alcohol is a preservative, not a sterilising agent

At low concentrations a measurable fraction of peptide can adsorb to glass and plastic surfaces, and the loss is largest exactly…

What a 1 mL syringe does that a 0.3 mL syringe does not

The graduation interval differs between barrel sizes, and a 1 mL barrel is frequently marked in two-unit steps. Reading one as…

The supply gap as a clinical event

Why the reason for stopping changes what happens afterwards.

Do you need the top of the ladder?

A plateau at an intermediate dose and a plateau at the maximum dose look identical from the outside and mean different things.

What STEP 5 tells us about maintenance, and what it does not

Dose reduction is not withdrawal, and the trials that tested withdrawal cannot be read as testing it.

Why "muscle-sparing" is a marketing term and not a measurement

The rule that a quarter of weight lost is lean tissue has been in textbooks for decades and does not survive close reading.

Gallstones during rapid weight loss: drug, or weight loss?

Pancreatitis is rare, was adjudicated in the outcome programmes, and did not show the imbalance early case reports suggested.

The advice is mostly reasonable. The certainty is not earned.

Almost every practical recommendation in circulation was established in a population that does not resemble the people now…

The convention nobody explains before handing over the vial

Dead space in the needle hub is a real and calculable loss, and it matters more at small volumes than anybody expects.

How a claim degrades between the bench and the listing

Every step between the laboratory report and the product page removes information, and the badge is the last step.

How a claim degrades between the bench and the listing

What a verification mark would have to carry to be checkable: a date, a lot, a method, a submitter and a link to the report.

Randomised withdrawal is the cleanest design in this field and the least discussed

A withdrawal trial answers a narrower question than it appears to. This piece states which question.

Why a result on one vial says less than the trade needs it to

Chain of custody, in a regulated setting, begins at sampling. Here it begins when the package arrives.

The lowest effective dose is a real concept with almost no data behind it

The commonest real-world strategy in this drug class is the least studied one.

Why people actually stop, in the order they actually stop

Real-world persistence figures, with their definitions stated, because the definitions are doing most of the work.

Randomised withdrawal is the cleanest design in this field and the least discussed

The regain trajectories, arm by arm, with the estimands named.

How a claim degrades between the bench and the listing

The Journal does not treat a badge as evidence and states so wherever it reports one.

Collapse temperature, and the hour of the cycle where shelf life is lost

Lyophilisation does not stop degradation. It slows every pathway by removing the solvent that most of them require, and the…

Two sessions a week, and the evidence behind the prescription

The recommendation survives scrutiny. The reasoning offered for it frequently does not.

Eating enough protein on a suppressed appetite is an arithmetic problem before it is a nutritional one

The practical difficulty is not knowing the target. It is meeting it on an appetite that has been pharmacologically reduced by…

Rapid weight loss moves eight analytes for reasons that have nothing to do with the drug

Three different explanations for the same abnormal number, and how to tell them apart.

EGFR, cystatin C, and the check on the check

What the renal and hepatic outcome programmes actually measured, and over what duration.

Glass, elastomer, aluminium: a three-material argument about one closure

Particulate matter is the oldest quality attribute in injectable manufacture and the one a private buyer is best placed to…

The intramuscular injection nobody intended

The insulin injection-technique literature is large, well conducted and directly transferable on questions of depth and tissue.…

Lipohypertrophy, and the absorption it ruins

A rotation scheme that is too complicated will not be followed. We describe the simple ones that are.

The incretin receptors, ranked by how much we actually know about them

The receptor is expressed in more tissues than the popular account allows, and that is the whole story.

The arithmetic behind every identity confirmation, worked in full

A peptide has a monoisotopic mass and an average mass, they differ by several daltons at this molecular size, and a certificate…

Twelve minutes or forty: what gradient slope buys

We set out the parameters a method disclosure would contain, all of which are known to whoever ran the sample and none of which…

What competing on one number does to a market

A market that competes on one measurement will optimise that measurement. There are legitimate ways to raise a purity figure…

The limits of mechanism: why receptor data will not tell you who responds

A catalogue of open questions, with an assessment of how likely each is to be resolved.

Pass, conform, comply: three words for three different claims

Statements of conformity are supposed to rest on a stated decision rule. Almost nothing in this trade states one.