Candesartan may offer neurocognitive protection against mild cognitive impairment

The ARB* candesartan was superior to the ACEi** lisinopril in improving neurocognitive function in older hypertensive adults with mild cognitive impairment (MCI), a study has shown.

“[C]andesartan was associated with better cognitive outcomes [vs] lisinopril, including one of two executive function measures, and in memory … These effects are independent of, but likely additive to [the BP-lowering effects of candesartan],” said the researchers. “[The positive effect on] memory suggests a role in amnestic disorders, such as Alzheimer’s disease (AD).”

After adjusting for systolic blood pressure (BP) and stratification variables, candesartan outdid lisinopril in improving executive function (effect size [ES], −12.0 seconds; p=0.01 [TMT*** Part B] and ES, −13.6 seconds; p=0.008 [TMT Part B – A]). [JAMA Network Open 2020;3:e2012252]

Additionally, there was less WML^# accumulation with candesartan vs lisinopril after adjusting for BP and stratification variables (0.2 mm³ vs 0.8 mm³) and for baseline levels (0.1 mm³ vs 0.6 mm³).

“Hypertension and executive impairment are associated with microvascular brain damage, and our study provides initial evidence that candesartan … protects against WML accumulation and vascular brain injury. However, … the between-group differences [were] not statistically significant,” they explained.

Candesartan was also superior to lisinopril in terms of episodic memory improvement, as reflected by the delayed recall (ES, 0.4; p=0.04) and retention indices (ES, 5.1; p=0.02) of the HVLT-R^##.

Compared with lisinopril, candesartan was associated with lower incidences of cough (8 percent vs 27 percent; p=0.005) and withdrawal due to adverse events (12 percent vs 28 percent; p=0.01). Conversely, skin rash incidence was higher with candesartan vs lisinopril (9 percent vs 1 percent; p=0.008).

Selective AT receptor blockade

The study randomized 176 participants (mean age 66 years, 57 percent women) 1:1 to receive escalating doses of oral candesartan (8 mg up to 32 mg) or lisinopril (10 mg up to 40 mg) QD for 12 months. Open-label antihypertensives^### were added as necessary to achieve a mean sitting BP of <140/90 mm Hg.

The superior effect of ARBs on cognitive function may be due to the differential blockade of the two angiotensin receptors (ie, AT₁ and AT₂) in the brain – AT₁ activation promotes neurotoxic mechanisms; AT₂ stimulation counteracts them, noted the researchers. The selective AT₁ receptor-blocking mechanism of ARBs may offer superior protection as opposed to concurrent lowering of both receptor activities with ACEIs, they pointed out.

Despite evidence reflecting the protective effect of BP lowering against cognitive decline, most excluded individuals with symptomatic CI, or did not compare drug regimens, noted the researchers. Other trials used the Mini-Mental State Exam as cognitive measure, which as per the researchers, “is rather insensitive to executive impairment and in detecting change over time. Hence, our study addresses a key gap in the literature.”

However, the findings are not generalizable to other drugs within the same drug classes evaluated, as the study did not aim to evaluate a class effect, they pointed out. “[Nonetheless,] ARBs in general, and candesartan in particular, offer an intriguing therapeutic possibility for cognitive disorders in relation to vascular brain injury.”

They called for larger and longer studies to gain further insight into the functional effects of candesartan. “It is … unclear if these effects are related to BP reduction or to possible pleiotropic BP-independent effects of certain antihypertensive medications … Such pleiotropic effects of antihypertensive drugs may be leveraged to repurpose drugs for cognitive disorders, including AD … Hence, further investigations of ARBs in this area are critical,” they said.