Candesartan versus Lisinopril on Neurocognitive Function in Older Adults with Mild Cognitive Impairment

Candesartan versus Lisinopril on Neurocognitive Function in Older Adults with Mild Cognitive Impairment
Bridget Williams, Pharm.D., Allina Health

Background: Observational studies suggest that angiotensin receptor blockers (ARBs) may provide protective effects on cognitive function in patients without impaired cognition. It is unclear whether this effect is due to overall benefits of blood pressure (BP) reduction or their specific mechanism of angiotensin II receptor blockade. One suggested mechanism for these protective effects includes candesartan’s selectivity for blockade of the AT1 receptor of the renin angiotensin system. This leads to increased activation of the AT2 receptor which is associated with axonal regeneration, neuronal repair and decreases in vascular inflammation. In addition to the benefits of AT2 receptor stimulation, ARBs have also been shown to reduce inflammation better than angiotensin-converting enzyme inhibitors (ACEI).

Objective: To compare the impact of candesartan vs. lisinopril on cognitive function in patients ages 55+ with hypertension and mild cognitive impairment.

Study Design: This double-blind randomized controlled trial aimed to compare the effects of 12 months of treatment with an ARB (candesartan) vs. an ACEI (lisinopril) in patients ages 55+ diagnosed with mild cognitive impairment and hypertension. From June 2014 to December 2018, 176 patients were randomized from prior antihypertensive therapy to candesartan or lisinopril provided in identical oral capsule formulations. Medications were escalated to a maximum of 32 mg candesartan once daily or 40 mg lisinopril once daily to achieve goal BP <140/90 mmHg. Additional open-label antihypertensive therapies were added as needed following study protocol to attain goal blood pressure control. The primary outcome was executive cognitive function. This was assessed with the Trail Making Test (TMT) and the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (EXAMINER) tool at baseline, 6 months, and 12 months. Secondary outcomes were episodic memory and microvascular brain injury. Episodic memory was measured with the Hopkins Verbal Learning Test-Revised (HVLT-R) at baseline, 6 months, and 12 months, and microvascular brain injury was visualized with magnetic resonance imaging (MRI) at baseline and 12 months. Patients were excluded if intolerant to any ACEI or ARB, diagnosed with dementia or any active medical or psychiatric condition deemed a safety risk by the study physician, had a systolic BP >200 mmHg or diastolic BP >110 mmHg, baseline serum creatinine >1.99 mg/dL, or baseline serum potassium >5.5 mEq/dL.

Results: Of 176 enrolled patients, 141 completed the trial, with no significant difference in dropout rates between groups. Both candesartan and lisinopril groups achieved similar BP control at the end of 12 months (mean systolic BP 134 vs 130 mmHg, P=0.2; mean diastolic BP 78 vs 77 mmHg, P=0.52). After adjusting for BP, race, additional antihypertensive drugs, and baseline cognitive test scores, candesartan was determined to be superior to lisinopril in executive function measured with the TMT-Part B tool (effect size = -12.8 [95% CI -22.5 to -3.1]), but not with the EXAMINER tool (effect size = -0.03 [95% CI -0.08 to 0.03]). Candesartan was also found to be superior to lisinopril in some measures of the secondary outcome, including delayed recall (effect size = 0.4 [95% CI 0.02 to 0.8]) and retention (effect size = 5.1 [95% CI 0.7 to 9.5]). MRI scans showed a non-significant lower rate of white matter lesion accumulation with candesartan compared to lisinopril (effect size = -0.3 [95% CI -0.6 to 0]).

Conclusions: Overall, the results suggest that candesartan may have a greater impact on executive function and episodic memory in older adults with hypertension and mild cognitive impairment compared to lisinopril. These results indicate that candesartan’s neurocognitive protective effects may be independent of BP reduction. Further studies are required to determine if cognitive protection is a class effect of ARBs.

Key Point: Twelve-month treatment with candesartan was associated with protection of executive function and memory in older hypertensive adults with diagnosed mild cognitive impairment compared to lisinopril titrated to equivalent goal BP. It is unclear whether these findings may be attributed to ARBs as a class effect, and more research is needed to determine whether the impact on cognitive function is clinically significant.


  1. Hajjar I, Okafor M, McDaniel D, et al. Effects of candesartan versus lisinopril on neurocognitive function in older adults with executive mild cognitive impairment: a randomized clinical trial. JAMA Netw Open. 2020;3(8):1-16. doi: 10.1001/jamanetworkopen.2020.12252.