Therapeutics

Telmisartan

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Overview

Name: Telmisartan
Synonyms: Micardis
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Boehringer Ingelheim
Approved for: Hypertension

Background

Telmisartan is an angiotensin II receptor antagonist marketed around the world to treat elevated blood pressure and reduce the possibility of cardiovascular risk associated with chronic hypertension. Telmisartan is an alternative medication for people who are unable to take angiotensin-converting enzyme (ACE) inhibitors. In March 2014, a generic version became available in the U.S. 

Angiotensin receptor blockers (ARBs) have been linked to reduced risk of AD. They 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 (e.g., Wharton et al., 2015; Barthold et al., 2018; also see Walker et al., 2020). Telmisartan use has been associated with a lower risk of AD specifically in African Americans, and of dementia in East Asians with diabetes and hypertension (Zhang et al., 2022; Liu et al., 2021).

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).  

Telmisartan has been proposed to slow AD pathogenesis by controlling cerebral blood flow, protecting the cerebral microvasculature, and reducing plaque formation in the brain (e.g., Baden et al., 2008; Mogi et al., 2008; Kurata et al., 2014). It acts via the peroxisome proliferator-activator receptor γ to reduce inflammation (Fu et al., 2023; Wang et al., 2020). Intranasal administration of telmisartan in the 5XFAD Alzheimer’s mouse model reduced amyloid burden and improved cognition (Torika et al., 2017).

Findings

Two clinical trials are evaluating telmisartan in Alzheimer's disease, both sponsored by academic medical centers, not the drug maker.

In spring 2014, a Phase 2 open-label drug repurposing study sponsored by the Alzheimer's Drug Discovery Foundation started up at three locations in Ontario, Canada. It enrolls 150 people with a clinical diagnosis of mild to moderate AD supported by an MRI scan consistent with that diagnosis. Participants take a one-year course of 40 or 80 mg of telmisartan or, as a comparator, 2, 4, or 8 mg per day of the angiotensin converting enzyme inhibitor (ACEI) antihypertensive drug perindopril. The primary outcome, besides safety, is ventricular enlargement as measured by MRI, to assess whether telmisartan slowed brain atrophy. Secondary outcomes are hippocampal, gray/white matter volume, and cognitive and functional measures. This trial is set to run until September 2023.

A Phase 1 study, sponsored by Emory University, started in April 2015 to enrolled 61 middle-aged African Americans who are at risk of Alzheimer's disease due to having both hypertension and a parent with Alzheimer's (Wharton et al., 2018). The study compared an eight-month course of either 20 mg or 40 mg telmisartan once daily to placebo for change in CSF angiotensin metabolites, Aβ and tau. Secondary outcomes included CSF markers inflammation, and structural and perfusion MRI. This trial finished in April 2022; results are not public.

For details, see clinicaltrials.gov.

Last Updated: 18 Oct 2023

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References

Paper Citations

  1. Wharton W, Goldstein FC, Tansey MG, Brown AL, Tharwani SD, Verble DD, Cintron A, Kehoe PG. Rationale and Design of the Mechanistic Potential of Antihypertensives in Preclinical Alzheimer's (HEART) Trial. J Alzheimers Dis. 2018;61(2):815-824. PubMed.
  2. 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.
  3. 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.
  4. 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.
  5. Walker VM, Davies NM, Martin RM, Kehoe PG. Comparison of Antihypertensive Drug Classes for Dementia Prevention. Epidemiology. 2020 Nov;31(6):852-859. PubMed.
  6. Zhang P, Hou Y, Tu W, Campbell N, Pieper AA, Leverenz JB, Gao S, Cummings J, Cheng F. Population-based discovery and Mendelian randomization analysis identify telmisartan as a candidate medicine for Alzheimer's disease in African Americans. Alzheimers Dement. 2022 Nov 4; PubMed.
  7. Liu CH, Sung PS, Li YR, Huang WK, Lee TW, Huang CC, Lee TH, Chen TH, Wei YC. Telmisartan use and risk of dementia in type 2 diabetes patients with hypertension: A population-based cohort study. PLoS Med. 2021 Jul;18(7):e1003707. Epub 2021 Jul 19 PubMed.
  8. 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.
  9. 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.
  10. Baden T, Yamawaki H, Saito K, Mukohda M, Okada M, Hara Y. Telmisartan inhibits methylglyoxal-mediated cell death in human vascular endothelium. Biochem Biophys Res Commun. 2008 Aug 22;373(2):253-7. PubMed.
  11. Mogi M, Li JM, Tsukuda K, Iwanami J, Min LJ, Sakata A, Fujita T, Iwai M, Horiuchi M. Telmisartan prevented cognitive decline partly due to PPAR-gamma activation. Biochem Biophys Res Commun. 2008 Oct 24;375(3):446-9. PubMed.
  12. Kurata T, Lukic V, Kozuki M, Wada D, Miyazaki K, Morimoto N, Ohta Y, Deguchi K, Ikeda Y, Kamiya T, Abe K. Telmisartan reduces progressive accumulation of cellular amyloid beta and phosphorylated tau with inflammatory responses in aged spontaneously hypertensive stroke resistant rat. J Stroke Cerebrovasc Dis. 2014 Nov-Dec;23(10):2580-90. Epub 2014 Sep 16 PubMed.
  13. Fu XX, Wei B, Cao HM, Duan R, Deng Y, Lian HW, Zhang YD, Jiang T. Telmisartan Alleviates Alzheimer's Disease-Related Neuropathologies and Cognitive Impairments. J Alzheimers Dis. 2023;94(3):919-933. PubMed.
  14. Wang ZF, Li J, Ma C, Huang C, Li ZQ. Telmisartan ameliorates Aβ oligomer-induced inflammation via PPARγ/PTEN pathway in BV2 microglial cells. Biochem Pharmacol. 2020 Jan;171:113674. Epub 2019 Oct 18 PubMed.
  15. Torika N, Asraf K, Cohen H, Fleisher-Berkovich S. Intranasal telmisartan ameliorates brain pathology in five familial Alzheimer's disease mice. Brain Behav Immun. 2017 Aug;64:80-90. Epub 2017 Apr 3 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. Subudhi BB, Sahu PK. Angiotensin Mediated Oxidative Stress and Neuroprotective Potential of Antioxidants and AT1 Receptor Blockers. Mini Rev Med Chem. 2016 Oct 24; PubMed.
  2. Liu J, Liu S, Tanabe C, Maeda T, Zou K, Komano H. Differential effects of angiotensin II receptor blockers on Aβ generation. Neurosci Lett. 2014 May 1;567:51-6. Epub 2014 Mar 27 PubMed.
  3. Torika N, Asraf K, Danon A, Apte RN, Fleisher-Berkovich S. Telmisartan Modulates Glial Activation: In Vitro and In Vivo Studies. PLoS One. 2016;11(5):e0155823. Epub 2016 May 17 PubMed.
  4. Böhm M, Schumacher H, Leong D, Mancia G, Unger T, Schmieder R, Custodis F, Diener HC, Laufs U, Lonn E, Sliwa K, Teo K, Fagard R, Redon J, Sleight P, Anderson C, O'Donnell M, Yusuf S. Systolic blood pressure variation and mean heart rate is associated with cognitive dysfunction in patients with high cardiovascular risk. Hypertension. 2015 Mar;65(3):651-61. Epub 2015 Jan 12 PubMed.
  5. Li W, Zhang JW, Lu F, Ma MM, Wang JQ, Suo AQ, Bai YY, Liu HQ. [Effects of telmisartan on the level of Aβ1-42, interleukin-1β, tumor necrosis factor α and cognition in hypertensive patients with Alzheimer's disease]. Zhonghua Yi Xue Za Zhi. 2012 Oct 23;92(39):2743-6. PubMed.
  6. Shindo T, Takasaki K, Uchida K, Onimura R, Kubota K, Uchida N, Irie K, Katsurabayashi S, Mishima K, Nishimura R, Fujiwara M, Iwasaki K. Ameliorative effects of telmisartan on the inflammatory response and impaired spatial memory in a rat model of Alzheimer's disease incorporating additional cerebrovascular disease factors. Biol Pharm Bull. 2012;35(12):2141-7. PubMed.
  7. 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.
  8. Torika N, Asraf K, Cohen H, Fleisher-Berkovich S. Intranasal telmisartan ameliorates brain pathology in five familial Alzheimer's disease mice. Brain Behav Immun. 2017 Aug;64:80-90. Epub 2017 Apr 3 PubMed.
  9. Hu W, Li Y, Zhao Y, Dong Y, Cui Y, Sun S, Gong G, Zhang H, Chai Q, Wang J, Liu Z. Telmisartan and Rosuvastatin Synergistically Ameliorate Dementia and Cognitive Impairment in Older Hypertensive Patients With Apolipoprotein E Genotype. Front Aging Neurosci. 2020;12:154. Epub 2020 Jun 9 PubMed.
  10. Sekar S, Mani S, Rajamani B, Manivasagam T, Thenmozhi AJ, Bhat A, Ray B, Essa MM, Guillemin GJ, Chidambaram SB. Telmisartan Ameliorates Astroglial and Dopaminergic Functions in a Mouse Model of Chronic Parkinsonism. Neurotox Res. 2018 Jul 13; PubMed. Correction.
  11. Wharton W, Anderson A, Hayden KM, Carmichael OT, Clark JM, Luchsinger JA, Espeland M, Yasar S. Effect of renin-angiotensin system antihypertensive medication use on cognitive function in diabetes mellitus with obesity or overweight: An ancillary study to the Action for Health in Diabetes (Look AHEAD) trial. Diabetes Obes Metab. 2022 Dec;24(12):2443-2453. Epub 2022 Sep 5 PubMed.
  12. Abdelkader NF, Abd El-Latif AM, Khattab MM. Telmisartan/17β-estradiol mitigated cognitive deficit in an ovariectomized rat model of Alzheimer's disease: Modulation of ACE1/ACE2 and AT1/AT2 ratio. Life Sci. 2020 Mar 15;245:117388. Epub 2020 Jan 30 PubMed.
  13. Abo-Youssef AM, Khallaf WA, Khattab MM, Messiha BA. The anti-Alzheimer effect of telmisartan in a hyperglycemic ovariectomized rat model; role of central angiotensin and estrogen receptors. Food Chem Toxicol. 2020 Aug;142:111441. Epub 2020 May 22 PubMed.
  14. Kikuchi K, Fujita Y, Shen X, Liu J, Terakawa T, Nishikata D, Niibori S, Ito T, Ashidate K, Kikuchi T, Kikuchi Y, Maeda T, Zou K, Komano H. Interaction between Angiotensin Receptor and β-Adrenergic Receptor Regulates the Production of Amyloid β-Protein. Biol Pharm Bull. 2020;43(4):731-735. PubMed.
  15. Khalifa M, Safar MM, Abdelsalam RM, Zaki HF. Telmisartan Protects Against Aluminum-Induced Alzheimer-like Pathological Changes in Rats. Neurotox Res. 2019 Jul 22; PubMed.