Therapeutics

Losartan

Overview

Name: Losartan
Synonyms: Cozaar®, MK0954
Chemical Name: 2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Merck
Approved for: Hypertension, diabetic neuropathy

Background

Losartan is an angiotensin II receptor blocker used to treat high blood pressure. It reduces the risk of stroke in people with hypertension and heart enlargement. It is also used to protect against kidney damage due to diabetes. Approved in 1995, losartan is available in branded and generic forms. In 2017, it was the ninth most prescribed medication in the U.S. Common side effects include muscle cramps, stuffy nose, dizziness, and back pain. Losartan crosses the blood-brain barrier.

Managing hypertension with medications reduces the risk of mild cognitive impairment (Jan 2019 news). Losartan other angiotensin receptor blockers (ARBs) act on the renin-angiotensin system, which regulates blood pressure in the body and brain. Angiotensin II receptors also mediate inflammation, blood-brain barrier maintenance, neuron survival. Genetic, epidemiologic, and biological evidence implicates changes in the brain renin-angiotensin system in Alzheimer’s disease (reviewed in Kehoe 2018). ARB use is associated with a reduced incidence of cognitive impairment, dementia, and AD (e.g., Wharton et al., 2015; Barthold et al., 2018; also see Walker et al., 2020). In people with mild cognitive impairment, use of ARBs, but not other antihypertensives, is linked to lower brain amyloid load and CSF tau (Hajjar et al., 2012; Hajjar et al., 2015).  

In animal models of AD, losartan given systemically attenuates brain inflammation and cognitive impairment, without affecting soluble Aβ or plaque load (e.g., Ongali et al., 2014) In another study, intranasal losartan reduced Aβ plaques and inflammatory markers in APP/PS1 mice, but no behavioral data were reported (Danielyan et al., 2010). In mice expressing a variant of the angiotensin-converting enzyme that raises the risk of AD in people, losartan prevented neurodegeneration (Oct 2020 news).

In other preclinical work, losartan reversed scopolamine-induced memory deficits in mice (Ababei et al., 2019), and reduced inflammation, perivascular Aβ deposits, and neurological deficits in hypertensive rats (Drews et al., 2019). Losartan also reportedly inhibits platelet-mediated Aβ aggregation, a possible contributor to cerebral amyloidosis (Donner et al., 2020).

Some animal studies suggest that losartan’s cognitive benefits depend on activation of the angiotensin IV receptor, which occurs downstream of angiotensin II receptor inhibition (Royea et al., 2017; Royea et al., 2020).

Findings

In 2013, the Phase 2 RADAR trial began testing the effects of one year of losartan treatment on brain structure in people clinically diagnosed with mild to moderate Alzheimer’s disease (Kehoe et al., 2018). All 228 participants started with a two-week, open-label dose titration to 100 mg losartan daily, the highest dose used for hypertension. Those who tolerated treatment went through a wash-out period, and were then randomized to drug or placebo. The primary outcome is change in whole brain volume on MRI; secondary outcomes include the number of white-matter hyperintensities and cerebral blood flow, tests of memory, cognitive function, activities of daily living and quality of life, along with safety and blood pressure monitoring. The study, carried out at multiple sites in the U.K., was completed in May 2019.

In September 2016, the Phase 2/3 Risk Reduction for Alzheimer’s Disease (rrAD) trial started to evaluate the effect of blood pressure control plus cholesterol lowering, with or without exercise, on cognitive health in people at risk for AD (Szabo-Reed et al., 2019). The trial is enrolling 513 participants without dementia but at high risk for AD due to a family history, or having self-reported subjective cognitive decline. They must be sedentary, and have high blood pressure, treated or untreated. The four-arm design will compare a regimen of supervised aerobic exercise versus stretching only, with or without losartan and a calcium channel blocker to lower blood pressure, plus atorvastatin. The trial will run for two years, with a primary endpoint of change in neurocognitive function on a composite of the ADCS-PACC and NIH Toolbox Cognition Battery. Secondary outcomes include domain-specific cognitive functions, whole brain and hippocampal volume on MRI, brain-blood flow, white-matter integrity, and functional connectivity. The trial will run through November 2021 at four sites in the U.S.

In April 2018, a Phase 2 trial began to measure the relationship between hypertension, intracranial blood flow, and Aβ accumulation in older adults. The study will compare the effects of standard blood pressure control using losartan and amlodipine to reduce systolic blood pressure to less than 130 mmHg, or intensive reduction to less than 120 mm Hg, for one year in 120 older participants with normal cognition. Primary outcomes will be changes in the variability of brain blood flow with each heartbeat, or intracranial pulsatility. Secondary outcomes include CSF Aβ and tau, brain perfusion, structural and functional MRI, measures of neurocognitive function, and patient-reported outcomes of physical and mental health. The trial is slated to end in October 2022.

Two small studies, one completed and one ongoing, are examining the effect of a single dose of losartan on emotional information processing and cognitive function, for the possible treatment of anxiety (Pulcu et al., 2019).

For details on losartan trials, see clinicaltrials.gov.

Last Updated: 23 Oct 2020

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References

News Citations

  1. SPRINT MIND Data Published, Follow-Up Extended
  2. New ACE Variant Speeds Neurodegeneration in Alzheimer’s Mice

Paper Citations

  1. . The Rationale and Design of the Reducing Pathology in Alzheimer's Disease through Angiotensin TaRgeting (RADAR) Trial. J Alzheimers Dis. 2018;61(2):803-814. PubMed.
  2. . Rationale and methods for a multicenter clinical trial assessing exercise and intensive vascular risk reduction in preventing dementia (rrAD Study). Contemp Clin Trials. 2019 Apr;79:44-54. Epub 2019 Mar 1 PubMed.
  3. . To INFINITY and Beyond: What Have We Learned and What Is Still Unknown About Blood Pressure Lowering and Cognition?. Circulation. 2019 Nov 12;140(20):1636-1638. Epub 2019 Nov 11 PubMed.
  4. . The Coming of Age of the Angiotensin Hypothesis in Alzheimer's Disease: Progress Toward Disease Prevention and Treatment?. J Alzheimers Dis. 2018;62(3):1443-1466. PubMed.
  5. . Modulation of Renin-Angiotensin System May Slow Conversion from Mild Cognitive Impairment to Alzheimer's Disease. J Am Geriatr Soc. 2015 Sep;63(9):1749-56. PubMed.
  6. . The association of multiple anti-hypertensive medication classes with Alzheimer's disease incidence across sex, race, and ethnicity. PLoS One. 2018;13(11):e0206705. Epub 2018 Nov 1 PubMed.
  7. . Comparison of Antihypertensive Drug Classes for Dementia Prevention. Epidemiology. 2020 Nov;31(6):852-859. PubMed.
  8. . Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series. Arch Neurol. 2012 Sep 10;:1-7. PubMed.
  9. . Association Between Angiotensin Receptor Blockers and Longitudinal Decline in Tau in Mild Cognitive Impairment. JAMA Neurol. 2015 Sep;72(9):1069-70. PubMed.
  10. . Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer's disease model. Neurobiol Dis. 2014 Aug;68:126-36. Epub 2014 May 5 PubMed.
  11. . Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease. Rejuvenation Res. 2010 Apr-Jun;13(2-3):195-201. PubMed.
  12. . A Comparative Study on the Memory-Enhancing Actions of Oral Renin-Angiotensin System Altering Drugs in Scopolamine-Treated Mice. Am J Alzheimers Dis Other Demen. 2019 Aug;34(5):329-336. Epub 2019 May 19 PubMed.
  13. . Intranasal Losartan Decreases Perivascular Beta Amyloid, Inflammation, and the Decline of Neurogenesis in Hypertensive Rats. Neurotherapeutics. 2019 Jul;16(3):725-740. PubMed.
  14. . The collagen receptor glycoprotein VI promotes platelet-mediated aggregation of β-amyloid. Sci Signal. 2020 Aug 4;13(643) PubMed.
  15. . Angiotensin IV Receptors Mediate the Cognitive and Cerebrovascular Benefits of Losartan in a Mouse Model of Alzheimer's Disease. J Neurosci. 2017 May 31;37(22):5562-5573. Epub 2017 May 5 PubMed.
  16. . Memory and cerebrovascular deficits recovered following angiotensin IV intervention in a mouse model of Alzheimer's disease. Neurobiol Dis. 2020 Feb;134:104644. Epub 2019 Oct 24 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. . AT2R's (Angiotensin II Type 2 Receptor's) Role in Cognitive and Cerebrovascular Deficits in a Mouse Model of Alzheimer Disease. Hypertension. 2020 Jun;75(6):1464-1474. Epub 2020 May 4 PubMed.
  2. . Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010;340:b5465. PubMed.
  3. . Angiotension receptor blockers reduce the risk of dementia. J Hypertens. 2014 Apr;32(4):938-47. PubMed.
  4. . Memory is preserved in older adults taking AT1 receptor blockers. Alzheimers Res Ther. 2017 Apr 26;9(1):33. PubMed.
  5. . Angiotensin-Receptor Blockers (ARBs) and risk of Alzheimer´s Disease: A meta-analysis. Curr Clin Pharmacol. 2020 Jan 31; PubMed.
  6. . Enalapril Alone or Co-Administered with Losartan Rescues Cerebrovascular Dysfunction, but not Mnemonic Deficits or Amyloidosis in a Mouse Model of Alzheimer's Disease. J Alzheimers Dis. 2016;51(4):1183-95. PubMed.
  7. . Effect of Resveratrol on Reactive Oxygen Species-Induced Cognitive Impairment in Rats with Angiotensin II-Induced Early Alzheimer's Disease †. J Clin Med. 2018 Oct 5;7(10) PubMed.
  8. . Transforming growth factor-β1 induces cerebrovascular dysfunction and astrogliosis through angiotensin II type 1 receptor-mediated signaling pathways. Can J Physiol Pharmacol. 2018 May;96(5):527-534. Epub 2018 Mar 5 PubMed.
  9. . Losartan improves cerebrovascular function in a mouse model of Alzheimer's disease with combined overproduction of amyloid-β and transforming growth factor-β1. J Cereb Blood Flow Metab. 2016 Jul 7; PubMed.
  10. . Losartan-induced hypotension leads to tau hyperphosphorylation and memory deficit. J Alzheimers Dis. 2014;40(2):419-27. PubMed.
  11. . Central angiotensin II-induced Alzheimer-like tau phosphorylation in normal rat brains. FEBS Lett. 2012 Oct 19;586(20):3737-45. PubMed.
  12. . ACE gene is associated with Alzheimer's disease and atrophy of hippocampus and amygdala. Neurobiol Aging. 2005 Aug-Sep;26(8):1153-9. PubMed.
  13. . Baseline Prevalence of Polypharmacy in Older Hypertensive Study Subjects with Elevated Dementia Risk: Findings from the Risk Reduction for Alzheimer's Disease Study (rrAD). J Alzheimers Dis. 2020;77(1):175-182. PubMed.
  14. . Brain angiotensin II and angiotensin IV receptors as potential Alzheimer's disease therapeutic targets. Geroscience. 2020 Oct;42(5):1237-1256. Epub 2020 Jul 22 PubMed.