Side effects from statin use caused by negative expectations of patients, says study

Most side effects from taking statins are nocebo, driven by the act of taking tablets rather than whether the tablets contain a statin, a study has found.

“Clinicians should not interpret symptom intensity or timing of symptom onset or offset (on starting or stopping statin tablets) as indicating pharmacological causation, because the pattern is identical for placebo,” the researchers said.

This study sought to examine daily symptom scores on statin, placebo, and no treatment in individuals who had abandoned statins. Sixty participants received 12 1-month medication bottles, four containing atorvastatin 20 mg, four placebo, and four empty tablets.

The researchers then measured daily symptom intensity for each using an app (scale 1–100). They also measured the nocebo ratio, defined as the ratio of symptoms induced by taking statins that was also induced by taking placebo.

Of the included participants, 49 completed the 12-month protocol. Their mean symptom score was 8.0 (95 percent confidence interval [CI], 4.7–11.2) in no-tablet months and was higher in statin months (16.3, 95 percent CI, 13.0–19.6; p<0.001) as well as in placebo months (15.4, 95 percent CI, 12.1–18.7; p<0.001), with no difference between the two (p=0.388). [J Am Coll Cardiol 2021;78:1210-1222]

The corresponding nocebo ratio was 0.90. Individual-patient daily data showed that neither symptom intensity on starting (odds ratio [OR], 1.02, 95 percent CI, 0.98–1.06; p=0.28) nor extent of symptom relief on stopping (OR, 1.01, 95 percent CI, 0.98–1.05; p=0.48) distinguished between statin and placebo.

Treatment discontinuation was comparable between statin and placebo (OR, 1.48, 95 percent CI, 0.85–2.62; p=0.173), as was subsequent symptom relief. Only eight patients stopped a statin month early and five who stopped a placebo month early. At 6 months after the trial, half of the participants (30 of 60, 50 percent) were back on statin treatment.

Possible origins of statin side effects were thus proposed. First, these side effects are a direct pharmacological effect; second, patients initiating statins may notice a chance increment in fluctuating background symptoms and correctly state that they have increased; third, a false association could be created through patients or doctors trying to test causation by starting or stopping tablets as an informal experiment; finally, patients may be primed to expect symptoms.

“The danger of the informal experimentation that is currently recommended in North America, Europe, and the UK is that even if there is a preplanned schedule and daily symptom scoring, without a placebo it is inevitable that nocebo symptoms will be misattributed to the statin,” the researchers said. [Eur Heart J 2020;41:111-188; https://tools.acc.org/statinintolerance/; https://www.england.nhs.uk/aac/wp-content/uploads/sites/50/2020/09/statin-intolerance-pathway-03092020.pdf]

“This phenomenon would unfortunately contribute to the 50 percent of statin starters who stop,” they added.

The current study was limited by the recruitment of participants with symptoms that arose within 2 weeks of commencing statins and the testing of a single statin at a single dose. In addition, the trial did not require blood samples “to avoid discouraging participation, to prevent delays to stopping tablets, and to maximize clinical applicability.”

“In future trials, a multiple-crossover trial design that includes a no-treatment arm as well as an active drug and placebo could prove useful in isolating side-effect profiles related to nonpharmacological factors,” the researchers said.