Not Taking It and Not Tolerating It

Studies of these drugs almost always count one thing: did the person stop. That merges two entirely different situations — someone whose body cannot tolerate the drug, and someone who simply is not taking it reliably. A Scottish study separated them, and found they have different predictors.^[1] Which means they need different responses, and until now have been indistinguishable in the data.

Why splitting them matters

A person who vomits every time they inject and gives up has a pharmacological problem. A person who keeps meaning to refill and does not has a logistical one. Both appear in a database as a discontinuation, and both get counted in the persistence figures this register has reported.

The interventions are opposite. The first needs a slower titration, a lower dose, or a different drug — the kind of change with randomized evidence behind it. The second needs reminders, cheaper refills, or fewer barriers between the prescription and the pharmacy. Applying either to the wrong person achieves nothing.

This study classified every treatment start in a national diabetes database into five mutually exclusive groups over one year: adherent, poor adherence, and three ways of discontinuing including a proxy for intolerance.

The two profiles

Two ways of ending treatment, and almost nothing in common between them.

If that is what is happening, it is directly actionable: the people most likely to be driven off these drugs by side effects are the ones for whom a slower or lower titration should be considered first. Nothing in this study tests that, and it is the obvious hypothesis it generates.

The chronic kidney disease association fits the same picture from a different direction — impaired clearance means more drug exposure for the same dose.

The finding that turns up twice

Female sex predicted intolerance here. In a separate US cohort we covered, women had lower odds of both persistence and adherence over twelve months — less than half are still taking it.

Different countries, different databases, different measures, and the same direction. That is worth more than either finding alone, and it runs against how this field is usually framed — trials over-recruit women, and the public conversation about these drugs is largely about women taking them.

Neither study explains it. If the lower-BMI mechanism is real, part of the answer may simply be that women are on average lighter and therefore receiving more drug per kilogram at the same dose — which would make the sex finding a body-size finding wearing different clothes. That is a hypothesis, and testing it would require dosing by weight, which nobody does.

The drug-by-drug part, and why to hold it loosely

Newer agents showed more favorable usage patterns. Poor adherence was more frequent with liraglutide, lixisenatide and exenatide than with semaglutide, and intolerance was most common with lixisenatide.

One more caution on the whole analysis: intolerance here is a proxy, inferred from the shape of prescribing records rather than read from a recorded diagnosis. Nobody wrote down that these patients could not tolerate the drug; the pattern of their prescriptions suggested it.