Possible Brain Side Effects of Repatha to Lower LDL Cholesterol

In 2015, the FDA approved evolocumab (Repatha) based on its remarkable ability to lower LDL (“bad”) cholesterol. It was initially intended for people with inherited high cholesterol or those at very high cardiovascular risk. In recent years, cardiologists have been moving the goal posts. They want to get LDL cholesterol as low as possible. It takes a statin plus a PCSK9 inhibitor like Repatha to achieve these goals.  Such a combo can achieve LDL-C levels below 50, sometimes below 30 mg/dL.  In recent years Repatha or a similar drug, Praluent (alirocumab) is also being prescribed to people who cannot tolerate statins. But could there be brain side effects of Repatha that were not discovered in early clinical trials?

Does Repatha Save Lives? What About Brain Side Effects?

The FDA originally approved Repatha based on the drug’s ability to lower LDL cholesterol dramatically. One condition of approval was that the manufacturer, Amgen, would conduct a clinical trial to find out whether people would also be less likely to die of heart attacks or strokes.

The results of that trial, FOURIER, were published in The New England Journal of Medicine (online March 17, 2017).  (If you were wondering, FOURIER stands for Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk.)

This randomized trial included 27,564 people at high risk of heart disease. The majority had already suffered at least one heart attack.

Half received high-intensity cholesterol-lowering treatment with a statin and in some cases ezetimibe (Zetia). In addition, they got placebo injections.

The other half received the same aggressive cholesterol-lowering treatment but their injections contained Repatha. After 48 weeks their LDL cholesterol had dropped to unprecedented low levels (the average was 30 but some patients had LDL levels even lower). After two years, heart attacks, strokes and the need for stents were reduced between 21 and 27 percent.

How Did Cardiologists React to This News?

Some physicians described these results as spectacular. Others, though, were more cautious. They notes that 9.8 percent of the patients getting Repatha and 11.3 percent on placebo experienced heart attacks, strokes, death or hospitalization. That means that roughly 1.5 people out of 100 got benefit.

Relative Risk vs. Absolute Risk:

Many people, including some health professionals, have a hard time reconciling an apparent contradiction. On the one hand, the headlines about Repatha underscored the relative risk reduction of 21 to 27 percent. On the other hand, fewer than 2 percent of the patients actually benefited from taking the drug.

Drug companies like to use relative risk numbers in their marketing efforts.

In one striking example, a Lipitor magazine ad proclaimed:

“In patients with multiple risk factors for heart disease, LIPITOR REDUCES RISK OF HEART ATTACK BY 36%*…”

On the surface, this sounds great. Who wouldn’t want to reduce the risk of a heart attack by more than a third? To a lot of people, this sounds like Lipitor would protect 36 patients out of 100 from having a heart attack. That would be terrific, no doubt. But the asterisk is important.

The fine print in the ad went on:

“That means in a large clinical study, 3 percent of patients taking a sugar pill or placebo had a heart attack compared to 2 percent of patients taking Lipitor.”

What this means is that if 100 people took the drug and 100 people took the placebo, there would be 2 heart attacks among Lipitor users and 3 among placebo takers–1 fewer heart attack over the course of the study (which actually had many more than 100 people and ran nearly five years). In other words, 99 people out of 100 who took the drug did not get any obvious heart attack protection. All of a sudden, the odds don’t seem as appealing as a 36 percent relative reduction in risk.

This certainly puts the Repatha results in a somewhat different light. That is especially true when you consider that in a separate analysis in the FOURIER trial, there was no difference between the two groups with respect to deaths.

What About General Side Effects?

The study did not show any significant increase in adverse effects of Repatha over placebo. The rate of side effects overall was high, however, reaching 77.4 percent in each group. Approximately one-fourth of the subjects suffered a serious reaction, although fewer than 2 percent of them needed to discontinue their injections.

Here are the results of of 8 placebo-controlled trials. The placebo reactions were surprisingly similar to the drug reactions. If you find that intriguing, you may want to read this new article that discusses the reporting system for adverse drug reactions.

Adverse Drug Reactions for REPATHA:

• Nasopharyngitis (inflammation of the nose and throat)..10%
• Upper respiratory tract infection………………………………..9.3%
• Influenza………………………………………………………………….7.5%
• Back pain…………………………………………………………………6.2%
• Injection site reactions………………………………………………5.7%
• Cough……………………………………………………………………..4.5%
• Urinary tract infection………………………………………………4.5%
• Sinusitis…………………………………………………………………..4.2%
• Headache…………………………………………………………………4.0%
• Myalgia…………………………………………………………………….4.0%

The placebo adverse reactions were roughly comparable to side effects reported for Repatha.

What About Brain Side Effects for Repatha?

As far as I can tell, there were no significant brain side effects reported in the clinical trials for Repatha.

But here is a question we received from a reader of our newspaper column:

Q. I developed severe depression while taking Repatha, the injectable cholesterol lowering drug. It took me a horrible nine months to realize the drug was making me suicidal. If I wasn’t sleeping, I was crying. I couldn’t think straight anymore.

My adult daughter helped me realize Repatha was causing my depression. I slowly started feeling better after stopping the injections. Of course, my doctors said the drug couldn’t have been responsible because depression wasn’t listed as a side effect.

A. Your doctor was correct that depression and suicidal thoughts do not appear in the official prescribing information for evolocumab (Repatha) or a similar drug, alirocumab (Praluent). Both are injectable medications that lower LDL cholesterol through a pathway called PCSK9.

We found one case report that mirrors your experience (Cureus, July 2, 2025). A woman with no prior history of depression began having crying bouts and persistent low mood within two weeks of starting Repatha. Three weeks after discontinuing the medication, these symptoms disappeared.

The authors of the Cureus case report introduce their article this way:

“Cholesterol is the principal component of myelin, and about 25% of the body’s cholesterol is stored in the brain. Despite the widespread use of cholesterol-lowering medications for cardiovascular protection, the functional effect of cholesterol deprivation in the brain is poorly understood. Existing literature highlights an inverse relationship between serum cholesterol levels and mood disorders; nonetheless, heterogeneous study designs and broad clinical settings make the association difficult to establish. Does the rate or the extent of cholesterol reduction influence neuropsychiatric outcomes? Could targeting different proteins lead to distinct results? These questions remain unanswered and warrant further investigation.”

The authors go on to say this about the brain side effects of Repatha:

“The present case report depicts an early-onset mood disorder attributed to the lipid-lowering medication Repatha in a patient without any history of previous mood disorders.

“Whether lipid-lowering medications could be a cause of mood disorders is debated in the literature. A recurrent trend has been observed between low cholesterol levels and mood disorders, particularly depression and increased suicidality. To define the trend, a meta-analysis of 32 cross-sectional studies found that individuals with depression had lower LDL-C values compared to individuals who were screened but did not meet the diagnostic criteria. Although statistically significant, an absolute difference of 4 mg/dl is modest and may hold limited clinical relevance.”

An analysis of the European pharmacovigilance database found that depression was reported for both evolocumab and alirocumab (Drug Safety, Dec. 22, 2020).

Here is what the authors shared:

“In this study, we investigated the safety profile of PCSK9Is, in terms of neurological and psychiatric ADRs [adverse drug reactions] through the analysis of data from the Eudravigilance database. The choice to evaluate these specific safety concerns has been driven by scientific evidences that demonstrated a higher risk of neurocognitive adverse events with these drugs. Indeed, according to the literature, it is biologically plausible that lipid-lowering therapies could impact brain function, causing cognitive adverse effects, and also considering that about 25% of the body’s cholesterol is found in the brain. Furthermore, cholesterol is the principal component of myelin, a fatty sheath that serves an essential role in cellular signalling and blood–brain barrier (BBB) integrity.”

“Key Points”

“Safety reports related to alirocumab and evolocumab and the occurrence of neuropsychiatric adverse drug reactions (ADRs) were retrieved from the Eudravigilance database and then analyzed.

“ADRs most commonly identified for alirocumab and evolocumab were headache, insomnia and depression. The statistical analysis applied revealed no difference between alirocumab and evolocumab and the probability of neuropsychiatric ADRs.

“Further data from real-life contexts needs to be collected in order to better characterize the neurocognitive safety profile of alirocumab and evolocumab.”

Detecting psychiatric side effects of medications can sometimes take years.

Another Analysis of Brain Side Effects of Repatha & Praluent:

In March of 2021 another report was published in Drug Safety about “Neurocognitive Adverse Drug Reactions” and both Repatha and Praluent.

The authors note:

“In this study, we investigated the safety profile of PCSK9Is, in terms of neurological and psychiatric ADRs [adverse drug reactions] through the analysis of data from the Eudravigilance database. The choice to evaluate these specific safety concerns has been driven by scientific evidences that demonstrated a higher risk of neurocognitive adverse events with these drugs.

“Our results have demonstrated that 22.7% of all ICSRs [Individual Case Safety Reports] reporting alirocumab or evolocumab as suspect described the occurrence of neuropsychiatric ADRs [adverse drug reactions]. The majority of reported ADRs were serious and were associated with female sex. Moreover, alirocumab was associated with an increased reporting probability of nervous and psychiatric ADRs compared with evolocumab.”

The authors call for further studies to evaluate the safety profile of Repatha and Praluent, especially with regard to “neurocognitive function.”

Final Words:

For many people who cannot tolerate statins, both Repatha and Praluent may be very good choices. And for those at high risk for cardiovascular disease, combining one of these PCSK9 inhibitors with a statin may very well reduce the risk for a heart attack or other cardiovascular event. No one should ever stop a medication without careful consultation with the prescriber!

In this week’s article titled “How Can You Trust Incomplete Drug Side Effect Information,” I discuss why brain side effect information is often delayed. I hope that is not the case with this class of cholesterol-lowering medications. Please share your own experience with either Repatha or Praluent in the comment section below.