Medications that reduce blood pressure are associated with fewer cases of amyotrophic lateral sclerosis, according to an epidemiological study in the November 10 JAMA Neurology online. Researchers from Kaohsiung Medical University in Kaohsiung City, Taiwan, mined that nation’s health insurance data to determine that people who had taken angiotensin-converting enzyme inhibitors (ACEIs) were less likely to be diagnosed with ALS. The authors are quick to note that the observational study cannot prove that ACEIs prevent or treat ALS. “We should consider this a first step to study the potential role of ACEIs in ALS risk,” wrote senior author Charles Tzu-Chi Lee in an email to Alzforum.
Lee, first author Feng-Cheng Lin, and colleagues were inspired to look at ACEIs by previous work in animals and people. One ACEI, temocapril, encourages neurite outgrowth in isolated rat spinal cords; another, captopril, slows neurodegeneration in an Alzheimer’s mouse model (Iwasaki et al., 2003; AbdAlla et al., 2013). In a small clinical trial of the ACEI perindopril in people with Parkinson’s disease, the treatment improved response to L-dopa treatment (Reardon et al., 2000). An observational study indicated that perindopril might slow down progression of Alzheimer's (O’Caoimh et al., 2014). No one had looked at ACEIs and ALS.
Taiwan offered a valuable opportunity. Because the majority of Taiwanese citizens receive health care through the country's National Health Insurance program, a database of records was available for the researchers to study. Diagnoses of ALS and other serious conditions require official certification in Taiwan, so the scientists could easily identify patients. Lin and colleagues examined records from 729 people newly diagnosed with ALS and 14,580 control records. In the ALS group, about 15 percent had taken ACEIs during the five years before their diagnosis. In contrast, about 18 percent of the controls had taken the inhibitors. The researchers defined low- and high-dose categories based on the standard daily dose for each drug recommended by the World Health Organization; people who had cumulatively ingested 450 days’ worth or more of ACEIs were analyzed separately from those who took less. The ALS risk for people with low ACEI doses was 83 percent of the controls' risk, and the risk for people on high doses was 43 percent of the controls'.
Other researchers were skeptical that ACEIs could influence ALS risk. The size of the effect was small, pointed out both Benjamin Wolozin of Boston University and Richard Bedlack of the Duke ALS Clinic in Durham, North Carolina. Bedlack noted that for people on low-dose ACEIs, the ALS risk was 83 percent that of those who did not take the medicines. However, because the 95 percent confidence interval for that 0.83 odds ratio ranged from 0.65 to 1.07, there might be no difference in ALS risk at all. “This finding will need to be replicated in order for most of us to believe that ACE inhibitors offer even the slightest protection against developing ALS,” wrote Bedlack in an email to Alzforum.
There is insufficient evidence to explain how ACEIs might influence ALS risk, Lee told Alzforum in an email. Suppressing hypertension itself is one possibility. High blood pressure is thought to damage the blood-brain barrier via inflammation and oxidative stress (reviewed in Pires et al., 2013). In the brain, blood pressure has been linked to dementia risk, though the evidence remains inconclusive (see Jun 2011 news story and AlzRisk). Hypertension promotes amyloid deposition and cognitive decline (see Aug 2007 news story and Aug 2014 news story). However, little work has been done on how blood pressure affects the spinal cord in ALS.
In addition to analyzing use of all ACEIs, the scientists focused on individual medications. The two most commonly prescribed were captopril and enalapril, taken by 41 and 46 people diagnosed with ALS, respectively. Of nine ACEIs, these were the only medications that passed statistical tests for reduction of ALS risk when analyzed separately from the other drugs. However, even those results were barely statistically significant, noted Wolozin. For enalapril the p value was 0.05, and for captopril it was 0.04. There is still a good possibility that the drugs do not affect ALS risk, said Wolozin, who praised the study design but concluded that the size of the effect was weak.
“Historically, epidemiological studies showing modest effects have not panned out [in prospective trials],” Wolozin wrote in an email to Alzforum (see full comment below). For example, observational studies suggested that non-steroidal anti-inflammatories (NSAIDs) could stave off dementia, but these drugs did not slow cognitive decline in trials (see May 2008 news story).
Even if ACEIs do cut the risk of ALS, that does not necessarily indicate they could be a treatment for people who already have the disease, Bedlack pointed out. Giulio Pasinetti of Mount Sinai School of Medicine in New York City agreed, advising that the potential side effects of ACEI use—which include fatigue, fainting, and headaches—would outweigh any theoretical benefit.—Amber Dance
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