Angiotensin Receptor Blockers and Epilepsy Risk: New Data

Angiotensin receptor blockers (ARBs), particularly losartan, are associated with a lower risk for incident epilepsy in patients with hypertension and no preexisting stroke or cardiovascular disease (CVD), new research suggested.

The study of more than two million patients with a diagnosis of primary hypertension who had received either an ARB, angiotensin-converting enzyme inhibitor (ACEI), beta-blocker, or calcium channel blocker (CCB) also showed significant association between ARB use and a lower rate of incident epilepsy in those with no preexisting history of stroke or CVD.

“The findings of this cohort study further demonstrated that ARBs, mainly losartan, may be associated with a lower incidence of epilepsy compared with ACEIs, beta-blockers, and DHP CCBs,” lead investigator Xuerong Wen, PhD, of the Department of Pharmacy Practice, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, and colleagues wrote.

“However, further pharmacological studies, including randomized clinical trials, are needed to establish antiepileptogenic properties of antihypertensive medications,” they add.

The study was published online on June 17, 2024, in JAMA Neurology. 

Epilepsy can be caused by brain injury including stroke or microvascular trauma. Losartan has previously been shown to block astrocyte activation and maintain the integrity of the blood brain barrier (BBB) in animal and human studies, the researchers noted.

A retrospective analysis of a German health administrative database showed a lower incidence of epilepsy in patients taking ARBs than in those taking other antihypertensives, but the study did not include data on baseline medical indications.

The researchers used a database of more than 20 million individuals enrolled in US commercial health plans or Medicare Advantage programs. The analysis included patient demographics, comorbid conditions, and use of other medications.

Investigators estimated propensity scores based on the probability of receiving an ARB, ACEI, beta-blocker, or CCB, in light of the baseline patient characteristics. 

Subgroup analyses by sex and age groups were also performed, and the analyses was repeated for patients with and without a diagnosis of stroke and preexisting CVD. 

Of the complete database, 2,261,964 patients were identified as initiating antihypertensive medications between from 2010 to 2017 (mean age, 62 years; 49.5% women). ACEIs were the most common antihypertensive class, followed by beta-blockers, CCBs, and ARBs.

Use of ARBs was associated with a decreased incidence of epilepsy than use of ACEIs (adjusted hazard ratio [aHR], 0.75; 95% CI, 0.58-0.96), beta-blockers (aHR, 0.70; 95% CI, 0.54-0.90), or other hypertensive medication classes (aHR, 0.72; 95% CI, 0.56-0.95), but not with CCBs.

A Probable Mechanism 

When the researchers assessed the association of each individual ARB and the incidence of epilepsy, they found losartan was the only agent that consistently showed lower epilepsy incidence. There was no statistically significant dose-response association with respect to high- vs low-dose losartan.

In the subgroup analysis based on age, sex, and diagnosis of stroke or CVD at baseline and CCB subclasses, they found no significant variations in the association between ARB use and epilepsy, except for sex, when ARBs were compared with ACEIs. In particular, compared with ACEI users, female users of ARBs had a 34% lower incidence of epilepsy (aHR, 0.66; 95%CI, 0.47-0.94). 

The authors cited animal studies demonstrating that the antiepileptic effects of losartan are attributable to suppressing the albumin-induced transforming growth factor beta signaling cascade, which reduces astrocyte activation and prevents permeability of the BBB. 

The renin-angiotensin system is not only important for blood pressure regulation but is increasingly recognized as a “key regulator” of seizure susceptibility. Moreover, BBB disruption may directly lead to seizures even in individuals without epilepsy. 

Limitations included potential unmeasured confounding factors. Important risk factors for epilepsy were also not available in the dataset, and the study used data from private health plans. So, findings may not be generalizable to other populations.

No source of study funding was listed. Wen reported no relevant financial relationships. The other authors’ disclosures are listed on the original paper. 

Batya Swift Yasgur MA, LSW, is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape Medical News and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).