Do High Blood Pressure Meds Reduce the Risk of ALS?

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

Comments

  1. Overall effect size reported here is modest. Historically, epidemiological studies showing modest effects have not panned out prospectively.

    Captopril and enalapril exhibited the statistically significant effects—the sample size for the other medications was generally too small to be informative. Captopril is brain-penetrant; enalapril is not brain-penetrant. If one is to interpret the results, then brain penetration must be factored into the equation with the resulting conclusion that brain penetration is not relevant to the putative mechanism of action.

    Much of the discussion focuses on scavenging of free radicals. This focus is disappointing because it ignores the major mechanism of action of ACEIs and instead focuses on a secondary hypothesis (free-radical scavenging) which is known to have no therapeutic value in ALS. A hypothesis based on free-radical scavenging is also unlikely to be relevant because enalapril does not get into the brain, which means that it would have to be putatively therapeutic without getting to the neurons and astrocytes to scavenge free radicals.

    A more likely putative mechanism of action would relate to the interaction between angiotensin II and its receptors. Many studies suggest that angiotensin receptors modulate neuroprotection, and it is easy to imagine that modulating such receptors could elicit neuroprotection in ALS. In AD, studies originally focused on ACEI, but then my studies focused attention on angiotensin receptor blockers, which directly act on the type I angiotensin receptor. This receptor inhibits neuroprotection, while the type II angiotensin receptor promotes neuroprotection. Studies examining angiotensin receptor blockers (ARBs) proved to be more significant than the ACEI results. In our studies, the brain-penetrant ARBs were associated with a reduction in the incidence of dementia, while the brain-non-penetrant ARBs were not associated with risk reduction. I am pleased to say that subsequent studies have supported these results. Pathologists (Dave Bennett) showed reduced AD pathology with ARBs, and some prospective trials for ARBs in the cardiovascular/stroke domain showed a reduced incidence of AD. What has definitely been shown in prospective clinical trials is that ARBs are associated with a reduced risk of diabetes, prospectively.

    In summary, the results are thought-provoking, although the discussion in the manuscript misses many key details.

    View all comments by Benjamin Wolozin

Make a Comment

To make a comment you must login or register.

References

News Citations

  1. AlzRisk Adds Fifth Factor to Database: Meta-Analysis of Hypertension
  2. Hypertension Begets Aβ, Begets Cardiovascular Damage
  3. Treating Midlife Hypertension Helps Preserve Cognition in Old Age
  4. NSAIDs in AD: Epi and Trial Data at Odds—Again

Paper Citations

  1. Iwasaki Y, Ichikawa Y, Igarash O, Ikeda K, Kinoshita M. Influence of temocapril on cultured ventral spinal cord neurons. Neurochem Res. 2003 May;28(5):711-4. PubMed.
  2. Abdalla S, Langer A, Fu X, Quitterer U. ACE Inhibition with Captopril Retards the Development of Signs of Neurodegeneration in an Animal Model of Alzheimer's Disease. Int J Mol Sci. 2013;14(8):16917-42. PubMed.
  3. Reardon KA, Mendelsohn FA, Chai SY, Horne MK. The angiotensin converting enzyme (ACE) inhibitor, perindopril, modifies the clinical features of Parkinson's disease. Aust N Z J Med. 2000 Feb;30(1):48-53. PubMed.
  4. O'Caoimh R, Healy L, Gao Y, Svendrovski A, Kerins DM, Eustace J, Kehoe PG, Guyatt G, Molloy DW. Effects of centrally acting angiotensin converting enzyme inhibitors on functional decline in patients with Alzheimer's disease. J Alzheimers Dis. 2014;40(3):595-603. PubMed.
  5. Pires PW, Dams Ramos CM, Matin N, Dorrance AM. The effects of hypertension on the cerebral circulation. Am J Physiol Heart Circ Physiol. 2013 Jun 15;304(12):H1598-614. Epub 2013 Apr 12 PubMed.

External Citations

  1. AlzRisk

Further Reading

Papers

  1. Ohrui T, Tomita N, Sato-Nakagawa T, Matsui T, Maruyama M, Niwa K, Arai H, Sasaki H. Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression. Neurology. 2004 Oct 12;63(7):1324-5. PubMed.
  2. Wharton W, Stein JH, Korcarz C, Sachs J, Olson SR, Zetterberg H, Dowling M, Ye S, Gleason CE, Underbakke G, Jacobson LE, Johnson SC, Sager MA, Asthana S, Carlsson CM. The effects of ramipril in individuals at risk for Alzheimer's disease: results of a pilot clinical trial. J Alzheimers Dis. 2012 Jan 1;32(1):147-56. PubMed.
  3. Solfrizzi V, Scafato E, Frisardi V, Seripa D, Logroscino G, Kehoe PG, Imbimbo BP, Baldereschi M, Crepaldi G, Di Carlo A, Galluzzo L, Gandin C, Inzitari D, Maggi S, Pilotto A, Panza F, . Angiotensin-converting enzyme inhibitors and incidence of mild cognitive impairment. The Italian Longitudinal Study on Aging. Age (Dordr). 2011 Dec 28; PubMed.
  4. Yamada K, Horita T, Takayama M, Takahashi S, Takaba K, Nagata Y, Suzuki N, Kanda T. Effect of a centrally active angiotensin converting enzyme inhibitor, perindopril, on cognitive performance in chronic cerebral hypo-perfusion rats. Brain Res. 2011 Nov 3;1421:110-20. PubMed.
  5. Davies NM, Kehoe PG, Ben-Shlomo Y, Martin RM. Associations of anti-hypertensive treatments with Alzheimer's disease, vascular dementia, and other dementias. J Alzheimers Dis. 2011;26(4):699-708. PubMed.
  6. Zou K, Michikawa M. Angiotensin-converting enzyme as a potential target for treatment of Alzheimer's disease: inhibition or activation?. Rev Neurosci. 2008;19(4-5):203-12. PubMed.

Primary Papers

  1. Lin FC, Tsai CP, Kuang-Wu Lee J, Wu MT, Tzu-Chi Lee C. Angiotensin-converting enzyme inhibitors and amyotrophic lateral sclerosis risk: a total population-based case-control study. JAMA Neurol. 2015 Jan;72(1):40-8. PubMed.

Annotate

To make an annotation you must Login or Register.