Therapeutics

Losartan

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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 an enlarged heart. 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 the brain. Angiotensin II receptors also mediate inflammation, blood-brain barrier maintenance, and 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, which may be independent of lowered blood pressure (e.g., Wharton et al., 2015; Barthold et al., 2018; also see Walker et al., 2020). ). However, meta-analyses do not support a benefit of ARBs over other classes of antihypertensives in preventing cognitive decline or dementia (Peters et al., 2020; Ding et al., 2020). In people with mild cognitive impairment, use of ARBs, but not other antihypertensives, was 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 other studies, intranasal or intraperitoneal losartan reduced Aβ plaques and inflammatory markers and stimulated neurogenesis in APP/PS1 mice, but no behavioral data were reported (Danielyan et al., 2010; Drews et al., 2021). 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). In Drosophila, losartan mitigated the toxicity of Aβ or a presenilin mutation independently of the renin-angiotensin pathway (Lee et al., 2021).

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 261 participants started with a two-week, open-label dose titration to 100 mg losartan daily, the highest dose used for hypertension. The 211 who tolerated treatment went through a wash-out period and were then randomized to drug or placebo. The primary outcome was change in whole-brain volume on MRI; secondary outcomes included 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. Losartan did not reduce the rate of brain atrophy or change any secondary measures (Kehoe et al., 2021).

In February 2017, 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 is comparing 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 is comparing 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 in AD, see clinicaltrials.gov.

Last Updated: 04 Nov 2021

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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. Kehoe PG, Blair PS, Howden B, Thomas DL, Malone IB, Horwood J, Clement C, Selman LE, Baber H, Lane A, Coulthard E, Passmore AP, Fox NC, Wilkinson IB, Ben-Shlomo Y. 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. Kehoe PG, Turner N, Howden B, Jarutyte L, Clegg SL, Malone IB, Barnes J, Nielsen C, Sudre CH, Wilson A, Thai NJ, Blair PS, Coulthard E, Lane JA, Passmore P, Taylor J, Mutsaerts HJ, Thomas DL, Fox NC, Wilkinson I, Ben-Shlomo Y, RADAR investigators. Safety and efficacy of losartan for the reduction of brain atrophy in clinically diagnosed Alzheimer's disease (the RADAR trial): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2021 Nov;20(11):895-906. PubMed.
  3. Szabo-Reed AN, Vidoni E, Binder EF, Burns J, Cullum CM, Gahan WP, Gupta A, Hynan LS, Kerwin DR, Rossetti H, Stowe AM, Vongpatanasin W, Zhu DC, Zhang R, Keller JN. 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.
  4. Pulcu E, Shkreli L, Holst CG, Woud ML, Craske MG, Browning M, Reinecke A. The Effects of the Angiotensin II Receptor Antagonist Losartan on Appetitive Versus Aversive Learning: A Randomized Controlled Trial. Biol Psychiatry. 2019 Sep 1;86(5):397-404. Epub 2019 Apr 17 PubMed.
  5. Kehoe PG. 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.
  6. Wharton W, Goldstein FC, Zhao L, Steenland K, Levey AI, Hajjar I. 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.
  7. Barthold D, Joyce G, Wharton W, Kehoe P, Zissimopoulos J. 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.
  8. Walker VM, Davies NM, Martin RM, Kehoe PG. Comparison of Antihypertensive Drug Classes for Dementia Prevention. Epidemiology. 2020 Nov;31(6):852-859. PubMed.
  9. Peters R, Yasar S, Anderson CS, Andrews S, Antikainen R, Arima H, Beckett N, Beer JC, Bertens AS, Booth A, van Boxtel M, Brayne C, Brodaty H, Carlson MC, Chalmers J, Corrada M, DeKosky S, Derby C, Dixon RA, Forette F, Ganguli M, van Gool WA, Guaita A, Hever AM, Hogan DB, Jagger C, Katz M, Kawas C, Kehoe PG, Keinanen-Kiukaanniemi S, Kenny RA, Köhler S, Kunutsor SK, Laukkanen J, Maxwell C, McFall GP, van Middelaar T, Moll van Charante EP, Ng TP, Peters J, Rawtaer I, Richard E, Rockwood K, Rydén L, Sachdev PS, Skoog I, Skoog J, Staessen JA, Stephan BC, Sebert S, Thijs L, Trompet S, Tully PJ, Tzourio C, Vaccaro R, Vaaramo E, Walsh E, Warwick J, Anstey KJ. Investigation of antihypertensive class, dementia, and cognitive decline: A meta-analysis. Neurology. 2020 Jan 21;94(3):e267-e281. Epub 2019 Dec 11 PubMed.
  10. Ding J, Davis-Plourde KL, Sedaghat S, Tully PJ, Wang W, Phillips C, Pase MP, Himali JJ, Gwen Windham B, Griswold M, Gottesman R, Mosley TH, White L, Guðnason V, Debette S, Beiser AS, Seshadri S, Ikram MA, Meirelles O, Tzourio C, Launer LJ. Antihypertensive medications and risk for incident dementia and Alzheimer's disease: a meta-analysis of individual participant data from prospective cohort studies. Lancet Neurol. 2020 Jan;19(1):61-70. Epub 2019 Nov 6 PubMed.
  11. Hajjar I, Brown L, Mack WJ, Chui H. Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series. Arch Neurol. 2012 Sep 10;:1-7. PubMed.
  12. Hajjar I, Levey A. Association Between Angiotensin Receptor Blockers and Longitudinal Decline in Tau in Mild Cognitive Impairment. JAMA Neurol. 2015 Sep;72(9):1069-70. PubMed.
  13. Ongali B, Nicolakakis N, Tong XK, Aboulkassim T, Papadopoulos P, Rosa-Neto P, Lecrux C, Imboden H, Hamel E. 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.
  14. Danielyan L, Klein R, Hanson LR, Buadze M, Schwab M, Gleiter CH, Frey WH. 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.
  15. Drews HJ, Klein R, Lourhmati A, Buadze M, Schaeffeler E, Lang T, Seferyan T, Hanson LR, Frey Ii WH, de Vries TC, Thijssen-van Loosdregt IA, Gleiter CH, Schwab M, Danielyan L. Losartan Improves Memory, Neurogenesis and Cell Motility in Transgenic Alzheimer's Mice. Pharmaceuticals (Basel). 2021 Feb 20;14(2) PubMed.
  16. Ababei DC, Bild V, Ciobică A, Lefter RM, Rusu RN, Bild W. 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.
  17. Drews HJ, Yenkoyan K, Lourhmati A, Buadze M, Kabisch D, Verleysdonk S, Petschak S, Beer-Hammer S, Davtyan T, Frey WH 2nd, Gleiter CH, Schwab M, Danielyan L. Intranasal Losartan Decreases Perivascular Beta Amyloid, Inflammation, and the Decline of Neurogenesis in Hypertensive Rats. Neurotherapeutics. 2019 Jul;16(3):725-740. PubMed.
  18. Donner L, Toska LM, Krüger I, Gröniger S, Barroso R, Burleigh A, Mezzano D, Pfeiler S, Kelm M, Gerdes N, Watson SP, Sun Y, Elvers M. The collagen receptor glycoprotein VI promotes platelet-mediated aggregation of β-amyloid. Sci Signal. 2020 Aug 4;13(643) PubMed.
  19. Royea J, Zhang L, Tong XK, Hamel E. 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.
  20. Royea J, Martinot P, Hamel E. 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.
  21. Lee SH, Gomes SM, Ghalayini J, Iliadi KG, Boulianne GL. Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Rescue Memory Defects in Drosophila-Expressing Alzheimer's Disease-Related Transgenes Independently of the Canonical Renin Angiotensin System. eNeuro. 2020 Nov-Dec;7(6) Print 2020 Nov-Dec PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Royea J, Lacalle-Aurioles M, Trigiani LJ, Fermigier A, Hamel E. 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. Li NC, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, Wolozin B. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010;340:b5465. PubMed.
  3. Chiu WC, Ho WC, Lin MH, Lee HH, Yeh YC, Wang JD, Chen PC, Health Data Analysis in Taiwan (hDATa) Research Group. Angiotension receptor blockers reduce the risk of dementia. J Hypertens. 2014 Apr;32(4):938-47. PubMed.
  4. Ho JK, Nation DA, Alzheimer’s Disease Neuroimaging Initiative. Memory is preserved in older adults taking AT1 receptor blockers. Alzheimers Res Ther. 2017 Apr 26;9(1):33. PubMed.
  5. Oscanoa TJ, Amado J, Vidal X, Romero-Ortuno R. Angiotensin-Receptor Blockers (ARBs) and risk of Alzheimer´s Disease: A meta-analysis. Curr Clin Pharmacol. 2020 Jan 31; PubMed.
  6. Ongali B, Nicolakakis N, Tong XK, Aboulkassim T, Imboden H, Hamel E. 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. Lin YT, Wu YC, Sun GC, Ho CY, Wong TY, Lin CH, Chen HH, Yeh TC, Li CJ, Tseng CJ, Cheng PW. 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. Ongali B, Nicolakakis N, Tong XK, Lecrux C, Imboden H, Hamel E. 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. Papadopoulos P, Tong XK, Imboden H, Hamel E. 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. Liu X, Wang Z, Xia Y, Yu G, Zeng K, Luo H, Hu J, Gong CX, Wang JZ, Zhou XW, Wang XC. Losartan-induced hypotension leads to tau hyperphosphorylation and memory deficit. J Alzheimers Dis. 2014;40(2):419-27. PubMed.
  11. Tian M, Zhu D, Xie W, Shi J. Central angiotensin II-induced Alzheimer-like tau phosphorylation in normal rat brains. FEBS Lett. 2012 Oct 19;586(20):3737-45. PubMed.
  12. Sleegers K, den Heijer T, van Dijk EJ, Hofman A, Bertoli-Avella AM, Koudstaal PJ, Breteler MM, van Duijn CM. 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. Vidoni ED, Kamat A, Gahan WP, Ourso V, Woodard K, Kerwin DR, Binder EF, Burns JM, Cullum M, Hynan LS, Vongpatanasin W, Zhu DC, Zhang R, Keller JN. 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. Royea J, Hamel E. 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.
  15. Vidoni ED, Kamat A, Gahan WP, Ourso V, Woodard K, Kerwin DR, Binder EF, Burns JM, Cullum M, Hynan LS, Vongpatanasin W, Zhu DC, Zhang R, Keller JN. 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.