Therapeutics

Candesartan

Overview

Name: Candesartan
Synonyms: Atacand, Candesartan cilexetil
Chemical Name: 2-ethoxy-1-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylic acid
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Mild Cognitive Impairment, Alzheimer's Disease
U.S. FDA Status: Mild Cognitive Impairment (Phase 2), Alzheimer's Disease (Phase 2)
Company: AstraZeneca, Takeda Pharmaceutical Company
Approved for: Hypertension, congestive heart failure

Background

Candesartan is an angiotensin II receptor antagonist used around the world to treat elevated blood pressure and congestive heart failure. Approved in 1997, the drug is available in generic form. The most common side effects are dizziness and headache. Candesartan crosses the blood-brain barrier.

Managing hypertension with medications reduces the risk of mild cognitive impairment (Jan 2019 news). Candesartan and 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, 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). 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).  

Preclinical work in models of chronic hypertension, stroke, kidney disease, and postoperative cognitive dysfunction support the idea that candesartan acts in the brain to attenuate brain inflammation and cognitive impairment, independent of its effect on blood pressure (Ahmed et al., 2018; Ahmed et al., 2018; Li et al., 2014).

In one AD mouse model, the ARB losartan improved memory and reduced plaque load (Wang et al., 2007), though in a similar model, candesartan reduced neuroinflammation but failed to reduce amyloid plaque or improve cognitive function (Trigiani et al., 2018). In 5XFAD mice, intranasal candesartan reduced brain inflammation and reduced amyloid burden by increasing Aβ uptake into microglia; this study did not assess cognition (Torika et al., 2018).

Findings

Several large studies have evaluated candesartan and cognitive decline in older adults. In the SCOPE trial of nearly 5,000 elderly people with mild hypertension, candesartan reduced nonfatal stroke by one-third compared to other hypertension treatment regimens, but did not change the trajectory of cognitive decline measured by change in the MMSE (Lithell et al., 2003). More extensive cognitive testing in a subset of 257 patients found a small slowing of decline on tests of attention and memory, but no difference in working memory or executive function (Saxby et al., 2008).

In the HOPE3 study of 2,361 older adults with marginally elevated blood pressure, no difference was detected in the rate of decline on tests of executive function or the Montreal Cognitive Assessment in people taking candesartan or placebo for six years (Mar 2019 news; Bosch et al., 2019).

The first trial to evaluate candesartan in people selected for mild cognitive impairment began in January 2008. The Phase 2 AVEC trial compared candesartan to the ACE inhibitor lisinopril or the diuretic hydrochlorothiazide on outcomes of cognition and blood flow in 53 older people with hypertension and cognitive impairment, but without dementia (Hajjar et al., 2009). Candesartan was titrated to a maximum of 32 mg daily, for one year, and all groups received additional anti-hypertensives as needed to achieve a target blood pressure of 140/90. The primary outcomes were tests of executive function and memory, cerebral blood flow, and vasoreactivity. The trial ran at one senior care facility in Massachusetts. According to published results, treatment with candesartan, but not lisinopril or hydrochlorothiazide, led to improved cerebral blood flow and performance on the Trail Making Test Part B measure of executive function (Hajjar et al., 2013).

From August 2014 to December 2018, the same investigators ran a Phase 2 trial comparing candesartan to lisinopril in people over 55 with high blood pressure and executive mild cognitive impairment. This study enrolled 176 participants, who received a maximum dose of 32 mg candesartan daily, with other medications as needed to achieve the target blood pressure. The primary outcome was change in executive function measured with the Trail Making Test Part B and the EXAMINER battery. Secondary measures included tests of episodic memory, language, and attention, MRI measures of white-matter hyperintensity, resting-state functional MRI, and ASL-MRI to measure cerebral perfusion. In groups with equally effective blood-pressure control, the candesartan-treated patients did better on the Trail Making Test Part B and HVLT, but not the EXAMINER battery, compared to those on lisinopril (Hajjar et al., 2020).

In June 2016, the Phase 2 CEDAR trial began to test candesartan’s effects in people with Alzheimer’s disease. The trial is enrolling 72 participants with mild cognitive impairment and PET or CSF evidence of brain amyloid, for a one-year, placebo-controlled treatment. Participants will receive the highest tolerated dose that maintains blood pressure above 100/40 and does not produce symptoms of hypotension, to a maximum of 32 mg daily. The primary outcomes measure tolerability, including symptoms of hypotension, changes in serum creatine or potassium, and the number of people who discontinue drug. Secondary outcomes include changes in CSF pTau181, Aβ42, and cytokines, plus measures of arterial and aortic stiffness. Other outcomes include clinical dementia rating, and tests of executive function and memory, MRI, and functional MRI. In January 2020, amyloid and tau PET were added. The study is expected to run through September 2021.

For more details, see clinicaltrials.gov.

Last Updated: 23 Oct 2020

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References

News Citations

  1. Too Little, Too Late? Blood Pressure and Cholesterol Meds Don’t Slow Cognitive Decline in 70s
  2. SPRINT MIND Data Published, Follow-Up Extended

Paper Citations

  1. . The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003 May;21(5):875-86. PubMed.
  2. . Candesartan and cognitive decline in older patients with hypertension: a substudy of the SCOPE trial. Neurology. 2008 May 6;70(19 Pt 2):1858-66. PubMed.
  3. . Effects of blood pressure and lipid lowering on cognition: Results from the HOPE-3 study. Neurology. 2019 Feb 27; PubMed.
  4. . The rationale and design of the antihypertensives and vascular, endothelial, and cognitive function (AVEC) trial in elderly hypertensives with early cognitive impairment: role of the renin angiotensin system inhibition. BMC Geriatr. 2009 Nov 18;9:48. PubMed.
  5. . Antihypertensive therapy and cerebral hemodynamics in executive mild cognitive impairment: results of a pilot randomized clinical trial. J Am Geriatr Soc. 2013 Feb;61(2):194-201. Epub 2013 Jan 25 PubMed.
  6. . Effects of Candesartan vs Lisinopril on Neurocognitive Function in Older Adults With Executive Mild Cognitive Impairment: A Randomized Clinical Trial. JAMA Netw Open. 2020 Aug 3;3(8):e2012252. PubMed.
  7. . 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.
  8. . 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.
  9. . 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.
  10. . Comparison of Antihypertensive Drug Classes for Dementia Prevention. Epidemiology. 2020 Nov;31(6):852-859. PubMed.
  11. . Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series. Arch Neurol. 2012 Sep 10;:1-7. PubMed.
  12. . Association Between Angiotensin Receptor Blockers and Longitudinal Decline in Tau in Mild Cognitive Impairment. JAMA Neurol. 2015 Sep;72(9):1069-70. PubMed.
  13. . Role of angiotensin system modulation on progression of cognitive impairment and brain MRI changes in aged hypertensive animals - A randomized double- blind pre-clinical study. Behav Brain Res. 2018 Jul 2;346:29-40. Epub 2017 Dec 8 PubMed.
  14. . RAS modulation prevents progressive cognitive impairment after experimental stroke: a randomized, blinded preclinical trial. J Neuroinflammation. 2018 Aug 13;15(1):229. PubMed.
  15. . Prophylactic angiotensin type 1 receptor antagonism confers neuroprotection in an aged rat model of postoperative cognitive dysfunction. Biochem Biophys Res Commun. 2014 Jun 20;449(1):74-80. Epub 2014 May 9 PubMed.
  16. . Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease. J Clin Invest. 2007 Nov;117(11):3393-402. PubMed.
  17. . Pleiotropic Benefits of the Angiotensin Receptor Blocker Candesartan in a Mouse Model of Alzheimer Disease. Hypertension. 2018 Nov;72(5):1217-1226. PubMed.
  18. . Candesartan ameliorates brain inflammation associated with Alzheimer's disease. CNS Neurosci Ther. 2018 Mar;24(3):231-242. Epub 2018 Jan 24 PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. . Angiotensin Receptor Blockade by Inhibiting Glial Activation Promotes Hippocampal Neurogenesis Via Activation of Wnt/β-Catenin Signaling in Hypertension. Mol Neurobiol. 2018 Jun;55(6):5282-5298. Epub 2017 Sep 7 PubMed.
  2. . Angiotensin II AT1 receptor blockade ameliorates brain inflammation. Neuropsychopharmacology. 2011 Mar;36(4):857-70. PubMed.
  3. . Angiotensin-Receptor Blockers (ARBs) and risk of Alzheimer´s Disease: A meta-analysis. Curr Clin Pharmacol. 2020 Jan 31; PubMed.
  4. . 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.
  5. . An integrative genome-wide transcriptome reveals that candesartan is neuroprotective and a candidate therapeutic for Alzheimer's disease. Alzheimers Res Ther. 2016 Jan 28;8:5. PubMed.
  6. . Candesartan Restores the Amyloid Beta-Inhibited Proliferation of Neural Stem Cells by Activating the Phosphatidylinositol 3-Kinase Pathway. Dement Neurocogn Disord. 2017 Sep;16(3):64-71. Epub 2017 Sep 30 PubMed.