Short answer: In the trials so far, no safety problem has been tied to very low LDL. In FOURIER, 47% of people on Repatha had LDL under 25 mg/dL at week 48, and a secondary analysis found no link between lower LDL and serious side effects over a median 2.2 years. In a substudy, memory and thinking tests were similar on Repatha and placebo over a median 19 months. Longer data are still limited.
The Repatha label says that in FOURIER, the heart outcomes trial in people with heart or blood vessel disease on statins, median LDL at week 48 was 26 mg/dL on Repatha, and 47% had LDL under 25 mg/dL.
Praluent's heart outcomes trial handled low values differently. The label says the dose was raised to 150 mg if LDL was 50 mg/dL or higher at month 2, lowered back to 75 mg after two readings under 25 mg/dL, and switched to placebo without telling the person after two readings under 15 mg/dL. That happened to 7.7% of people on Praluent. This was a rule for the trial, not a dosing instruction in the label.
Giugliano and colleagues grouped 25,982 FOURIER patients by the LDL they reached at 4 weeks and followed them for a median of 2.2 years.
| LDL reached | Share of patients |
|---|---|
| Under 0.5 mmol/L (about 19 mg/dL) | 10% |
| 0.5 to under 1.3 mmol/L | 31% |
| 1.3 to under 1.8 mmol/L | 13% |
| 1.8 to under 2.6 mmol/L | 29% |
| 2.6 mmol/L (about 100 mg/dL) or higher | 17% |
Heart events kept falling as LDL went lower, down to the lowest 1% (under 0.2 mmol/L). The authors found no significant link between the LDL reached and serious side effects or any of nine other safety events they had chosen in advance. This is a secondary analysis of one trial, run by the trial group and funded by Amgen, the maker of Repatha.
A common worry is the brain, which is rich in cholesterol. The Repatha label reports EBBINGHAUS, a substudy of 1,974 FOURIER patients, in which Repatha was not worse than placebo on selected tests of thinking. The published trial followed 1,204 patients for a median of 19 months: the main score for planning and working memory changed by -0.21 on Repatha and -0.29 on placebo, and memory and reaction-time scores did not differ. The authors found no link between LDL level and cognitive change.
Nineteen months is short compared with how long people may stay on these medicines, and the tests cover selected skills rather than every kind of thinking problem.
Neither the Praluent nor the Repatha label sets a lower LDL limit or says to stop when LDL is very low. Whether a very low result changes the plan is a question for the prescriber. Keeping each LDL result next to the dose history in Dose Track makes it easier to see the trend over time.
Read more on Dose Track: Repatha side effects · Praluent side effects · LDL cholesterol · Lipid panel