Candesartan Shows Signs of Neuroprotection in Older Adults With MCI and Hypertension

July 29, 2020

Compared to treatment with lisinopril, those treated with the angiotensin receptor blocker candesartan showed improvements on the Trial Making Test part A and B and Hopkins Verbal Learning Test-Revised delayed recall.

Ihab Hajjar, MD

Data from a randomized, double-blind, clinical trial suggest that treatment with candesartan (Atacand; AstraZeneca) may offer a unique method of neurocognitive protection in older adults with executive mild cognitive impairment (MCI) and hypertension.1

The results of the trial, dubbed CALIBREX (Candesartan vs. Lisinopril Effects on the Brain and Endothelial Function in Executive MCI; NCT01984164), showed that superior cognitive outcomes were associated with 32-mg candesartan, an angiotensin receptor blocker, compared with 40-mg lisinopril, an angiotensin-converting enzyme (ACE) inhibitor.

Of the 141 participants who completed the trial, those randomized to candesartan reported improved performance on the Trial Making Test part A and B (TMT B-A), and on Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recall. The dataset included individuals aged 55 years or older.

The results were presented virtually at the Alzheimer’s Association International Conference (AAIC) 2020 annual meeting by Ihab Hajjar, MD, associate professor and geriatrician, Division of General Medicine and Geriatrics, Emory University Department of Medicine.

Participants were withdrawn from prior antihypertensive therapy before randomization to escalating doses of their randomized agent. They were additionally allowed to add open-label antihypertensive drugs as needed to achieve blood pressure control. The groups underwent neuropsychological assessments at baseline, 6 and 12 months. The primary outcome was executive function, as measured by the TMT B-A, and secondary outcomes were episodic memory, as measured by HVLT-R, and neuroimaging evidence of microvascular brain injury reflected by white matter lesions (WML).

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After 12 months, those in the candesartan group showed improved cognitive performance on the TMT B-A, with a reduction of 16.8 seconds (95% CI, —30.3 to –3.3) while the lisinopril group reported worsened performance, with an increase of 11.5 seconds (95% CI, –3.0 to 26.0; P = .008). Additionally, HVLT-R delayed recall improved for the candesartan group by 1.0 (95% CI, 0.3—1.5) while the lisinopril group improved by 0.3 (95% CI, –0.3 to 1.0; P = .026) at the same time point.

The other secondary outcome, change in WML volume, displayed no significant changes with candesartan (0.2 mm3; 95% CI, —0.2 to 0.7), while the lisinopril group experienced a marked increase (0.9 mm3; 95% CI, 0.4—1.4; P = .06.) Although control of hypertension was deemed equivalent between the groups, more participants withdrew from the lisinopril group.

Data presented earlier this year from the CALIBREX trial suggested that candesartan and lisinopril offer gender differences in their vascular effects, based on measurements of arterial stiffness. Ultimately, those data showed that pulse wave velocity was reduced after 1 year in both men (baseline: 9.4 m/s [±3.6]; 1 year: 9.0 m/s [±2.3]; P = .13) and women (baseline: 9.3 m/s [±3.1]; 1 year: 8.6 m/s [±2.3]; P = .063) treated with lisinopril, whereas with candesartan, PWV did not change in men (baseline: 8.8 m/s [±2.7]; 1 year: 9.0 m/s [±2.4]; P<.002) but increased in women (baseline: 8.5 m/s [±2.6]; 1 year: 9.0 m/s [±2.2]; P <.002). Overall, the change in systolic blood pressure after 1 year with candesartan and lisinopril (P = .82).2

The neuroprotective effects of hypertension control in adults on cognitive decline and dementia have been demonstrated previously. In 2019, a cohort study including more than 4700 patients over 24 years suggested that those with midlife to late-life hypertension, or midlife hypertension and late-life hypotension, are at a higher risk for incident dementia compared to those with normal blood pressure levels in those periods. The hazard ratios (HRs) incident dementia among those with mid- and late-life hypertension and those with mid-life hypertension and late-life hypotension were 1.49 (95% CI, 1.06-2.08) and 1.62 (95% CI, 1.11-2.37), respectively. The authors noted that this association between late-life blood pressure and cognition may ultimately be dependent upon the chronicity of prior hypertension.3

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1. Amran A, Lin Y, Kim Y, Bernstam E, Jiang X, Schulz PE. Influenza Vaccination is associated with a reduced incidence of Alzheimer’s Disease. Presented virtually at AAIC 2020. Poster 48046.

2. Roger S, Mehta A, Dhindsa DS, Hajjar I, Quyyumi AA. Gender Differential Effects of Candesartan and Lisinopril on Arterial Stiffness in Hypertensive Subjects. Arteriosclerosis, Thrombosis, and Vascular Biology. 2020;40:A389.

3. Walker KA, Sharrett AR, Wu A, et al. Association of midlife to late-life blood pressure patterns with incident dementia. JAMA. 2019;322(6):535-545. doi: 10.1001/jama.2019.10575.