But whether drug has benefit earlier in the disease process is unknown

Patients with clinically diagnosed mild-to-moderate Alzheimer’s disease (AD) who were treated with losartan had no reduction in brain atrophy at 12 months compared with placebo, the randomized, double-blind RADAR trial found.

Mean brain volume reduction was 19.1 mL in the losartan group and 20.0 mL in the placebo group, reported Patrick Kehoe, MD, of the University of Bristol, England, and co-authors. The difference in total volume reduction between groups was –2.29 mL (95% CI –6.46 to 0.89; P=0.14), they wrote in Lancet Neurology.

“To our knowledge, this study is the first to evaluate the potential therapeutic value of an angiotensin II receptor antagonist in Alzheimer’s disease using an objective MRI-based primary outcome,” the researchers said. “This study suggests that 12 months of treatment with losartan is ineffective in reducing the rate of brain atrophy in individuals with mild-to-moderate Alzheimer’s disease.”

“There is not enough evidence currently to exclude a potential benefit of losartan, or related drugs, if administered for a longer period or in participants with less advanced disease (e.g., mild cognitive impairment due to prodromal Alzheimer’s disease),” Kehoe and colleagues added. “Further research is needed to inform whether primary care-based interventions for hypertension and other cardiovascular conditions, which include angiotensin II lowering approaches, might be amenable to primary intervention opportunities to reduce the incidence and progression of Alzheimer’s disease, rather than being used as treatments later in the disease course.”

The researchers randomized 261 patients with clinically diagnosed AD between July 2014 and May 2018 to either placebo (n=106) or losartan 100 mg daily (n=105) for 12 months. Patients already receiving angiotensin-converting enzyme (ACE) inhibitors, angiotensin II type 1 receptor antagonists, or potassium-sparing diuretics were excluded from the study.

Women made up 37% of the placebo group and 43% of the losartan group. Age was under 70 in 37% of each group, while 24%-26% were older than 79. Years since diagnosis were 1.10 for the placebo group and 1.38 for losartan. Mini Mental State Examination (MMSE) scores at baseline were a mean of 22 in both groups. About half of participants in both groups were hypertensive at baseline.

The primary outcome, change in whole brain volume at 12 months, was analyzed with MRI data for 171 participants.

Blood pressure levels at baseline were similar for both groups (mean 136/78 for placebo and 138/79 mm Hg for losartan), but at 12 months, greater reductions were seen in the losartan group compared to placebo (−6.96 mm Hg systolic and −3.59 mm Hg diastolic; P<0.0001 for both comparisons).

As with volume, similar deterioration over 12 months was seen for both groups on cognitive and activity of daily living measures, with no between-group differences. Reported serious adverse events were comparable between the losartan and placebo groups.

In an accompanying editorial, Charles DeCarli, MD, of the University of California at Davis, Sacramento, wrote that the “investigation of the utility of ACE inhibitors and angiotensin receptor blockade for the prevention of dementia should continue. It will be important to identify the patient groups that might benefit the most, such as those with vascular cognitive impairment, and to use a long follow-up to identify successful therapeutic approaches of what we are learning is the complex pathophysiology of, dementia.”

Two lessons can be learned from this negative trial, DeCarli suggested. “The lack of efficacy of losartan on improving cognition or on neuroimaging outcomes in this trial probably reflects the low prevalence of concurrent cerebrovascular disease in the study cohort,” he wrote. “Despite other effects identified for this drug class in previous studies, reduced blood pressure is likely to be its major mechanism of dementia prevention.”

“Second, hypertension affects the brain earlier in life (mean age 40 years) and probably has a prolonged and cumulative effect on brain function, needing early diagnosis and treatment, and prolonged observation to assess therapeutic relevance,” DeCarli continued. “For example, a review of the data from SPRINT MIND clearly shows little difference in the effect of standard versus intensive blood pressure control before year 4 of the study, but increasing differences up to year 7, indicating the probable need for longer follow-up for studies aimed at blood pressure modulation.”

SPRINT MIND compared incident probable dementia in hypertensive adults with systolic blood pressure goals of <120 versus <140 mm Hg over median follow-up of 5.11 years. Primary analysis showed no difference in incident diagnoses of probable dementia, but secondary analysis suggested possible benefit in mild cognitive impairment (MCI). SPRINT MIND authors noted that “some caution should be exercised in interpreting this result, both because MCI was not the primary cognitive outcome of the trial and because it is not clear what this effect may mean for the longer-term incidence of dementia.”

Losartan is used as therapy for hypertension, which is considered a risk factor for dementia, but other mechanisms have been proposed to account for a possible effect on cognition. Inhibition of angiotensin-converting enzyme reduces angiotensin II, which mediates hypertensive effects but may also be involved in inflammatory and oxidative stress responses. Blocking angiotensin II receptors is another approach to minimizing these deleterious effects, and it may be more effective.

A 2020 study of candesartan (angiotensin receptor blockade) versus lisinopril (ACE enzyme inhibition) in people with mild cognitive impairment concluded that an effect likely independent of blood pressure lowering led to improvement on 12-month cognitive performance for candesartan in the comparison, though white matter changes did not differ for the two agents.

A 2020 meta-analysis of the effects of different antihypertensive class medications on cognitive decline reported conflicting evidence regarding the best antihypertensive class for optimizing cognition, and summarized findings as supporting “clinical freedom in the selection of antihypertensive regimens to achieve blood pressure goals.”

Limitations of the RADAR study include its 12-month duration, which may have been too short, and its relatively small study size.

  1. Patients with clinically diagnosed mild-to-moderate Alzheimer’s disease (AD) who were treated with losartan had no reduction in brain atrophy at 12 months compared with placebo, the randomized, double-blind RADAR trial found.

  2. Available evidence cannot exclude a potential benefit of losartan or related drugs on cognitive decline when administered for a longer period in patients with less advanced disease, the authors noted.

Paul Smyth, MD, Contributing Writer, BreakingMED™

The study was funded by the Efficacy and Mechanism Evaluation Program (U.K. Medical Research Council and National Institute for Health Research).

Kehoe reported grants from the National Institute of Health Research during the conduct of the study; being a non-funded co-investigator of the ongoing Alzheimer’s Association-funded HEART phase 1b study of telmisartan and its use as an intervention against the renin–angiotensin system in African American people at risk of developing dementia by parental history; and having previously undertaken advisory work for Novartis in their development and intended trialling of dual acting inhibitors of Angiotensin Receptor Blockers and neprilysin (LCZ696) for the treatment of heart failure.

DeCarli declared no competing interests.

Cat ID: 130

Topic ID: 82,130,730,130,33,192,255,925