Beta-Blockers Tied to Delayed Huntington’s Disease Progression

Beta-blocker therapy was associated with a lower annualized hazard of receiving a clinical diagnosis of Huntington’s disease and a slower rate of symptom worsening, observational data showed.

In a group of people with genetically confirmed, premanifest Huntington’s disease, the annualized hazard of receiving a motor diagnosis was significantly lower for beta-block users than matched nonusers (HR 0.66, 95% CI 0.46-0.94, P=0.02), according to Jordan Schultz, PharmD, of the University of Iowa in Iowa City, and co-authors.

Among Huntington’s patients with early motor manifestations, beta-block users had a slower mean annualized worsening in total motor scores, total functional capacity scores, and symbol digit modalities test scores compared with matched nonusers, the researchers reported in JAMA Neurology.

Huntington’s is an autosomal dominant genetic disorder caused by extended cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin (HTT) gene. The number of CAG repeats in the HTT gene is inversely correlated with the age when neurologic symptoms start and how fast Huntington symptoms progress after onset.

The disease is characterized by progressive motor, cognitive, and psychiatric decline. Three treatments are approved to treat Huntington’s-related chorea — tetrabenazine (Xenazine), deutetrabenazine (Austedo), and valbenazine (Ingrezza) — which inhibit the vesicular monoamine 2 transporter (VMAT2) pathway,

The autonomic nervous system may be a novel target to help slow Huntington’s progression, Schultz observed.

“Patients with Huntington’s disease are known to have imbalances of the autonomic nervous system, but the therapeutic implications of this imbalance are still being investigated,” he told MedPage Today.

The findings suggest that beta-blockers and other drugs that help restore balance to the autonomic nervous system may have therapeutic benefits, Schultz noted.

“Given that there are currently no disease-modifying treatments for Huntington’s disease, the possibility for a class of medications that are inexpensive and have a well-established safety profile to potentially fill that void is very exciting,” he said.

Schultz and colleagues evaluated participants of Enroll-HD, a large observational research study that started in 2011. They included propensity score-matched groups of patients with premanifest Huntington’s and early motor-manifest Huntington’s who were either users or nonusers of beta-blockers.

All participants had a CAG repeat length between 36 and 55. People who had uninterrupted use of a beta-blocker for more than 1 year were considered beta-blocker users.

The premanifest Huntington’s group included 174 beta-blocker users (66% were women) with a mean age of 46 and a mean CAG repeat length of 41.1, matched with 174 nonusers. About 45% of participants in both groups had a hypertension diagnosis. Users were taking beta-blockers for about 7 years on average, most commonly propranolol, metoprolol, or bisoprolol. Hypertension was the most common indication for beta-blocker use.

The early motor-manifest Huntington’s group had 149 beta-blocker users (42% were women) with a mean age of 59 and a mean CAG repeat length of 42, matched with 149 nonusers. Metoprolol was the most common beta-blocker in this group followed by bisoprolol and propranolol, and hypertension was again the most common indication.

In the early motor-manifest Huntington’s group, the mean length of follow-up was 4.15 years for beta-blocker users and 5.19 years for nonusers. Beta-blocker users had slower mean annualized worsening in the following tests:

• Total motor score: mean difference (MD) of -0.45 points
• Total functional capacity score: MD of 0.10 points
• Symbol digit modalities test: MD of 0.33 points

Post hoc analyses did not show significant beneficial effects of other antihypertensive drug classes that impact the autonomic nervous system — angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) — in patients with either premanifest or motor-manifest Huntington’s disease.

The study could not establish causality or determine mechanisms to account for the relationships seen in this study, Schultz and co-authors acknowledged. Drug dose effects could not be determined.

In addition, selection bias may have occurred as beta-blocker users may represent people who seek out or receive better quality healthcare, they noted. Enroll-HD data did not include information about heart rate or blood pressure, and it’s unclear how those variables might have influenced results.