Losartan Fails to Reduce Brain Atrophy in Patients with Mild-to-moderate Alzheimer's Disease

Pavankumar Kamat

November 18, 2021

In a phase 2 trial, losartan treatment for 12 months was well tolerated but failed to reduce the rate of brain atrophy in patients with mild-to-moderate Alzheimer's disease (AD). The findings were published in The Lancet Neurology .

The double-blind, multicentre, phase 2 RADAR trial included 261 patients aged 55 years or older who were previously untreated with angiotensin II receptor blockers and diagnosed with mild-to-moderate AD, enrolled across 23 UK NHS hospital trusts. Following a 4-week, open-label phase of active treatment and washout, 211 participants were randomly assigned (1:1) to receive either 100 mg losartan (after an initial two-dose titration) or placebo daily for 12 months.

Primary outcome was the change in brain volume from baseline to 12 months, quantified using volumetric MRI and determined by boundary shift interval (BSI) analysis.

The mean brain volume reduction from baseline to 12 months was 19.1 (standard deviation [SD], 10.3) mL in the placebo group versus 20.0 (SD, 10.8) mL in the losartan group, the difference between the groups being non-significant (adjusted mean difference, 1.23 [95% CI −1.72 to 4.19] mL; P=0.41). Furthermore, the difference in total volume reduction (BSI) between the groups was also non-significant (difference, −2.29 [95% CI −6.46 to 0.89] mL; P=0.14).

In a substudy of 105 participants, there was no difference in the volume of white matter hyperintensities between the groups (P=0.70). Losartan also failed to confer any therapeutic benefit in hippocampal atrophy and ventricular volume. At 12 months, the losartan group demonstrated greater reductions in systolic and diastolic blood pressures compared with the placebo group.

The frequency of serious adverse events (AEs) in the intervention phase was comparable between the losartan group and the placebo group (22 vs 20 events). The most common serious AEs included infections, mechanical injury, neuropsychiatric events, and gastrointestinal events. One death was recorded in each group, unrelated to the treatment.

Explaining the potential reason for losartan's failure, the authors stated: "It is possible that losartan did not penetrate the blood-brain barrier as much as anticipated; therefore, although peripherally active, as seen by the reductions in blood pressure in the losartan group, it was not able to act more directly in the brain where it was intended to reduce disease-related atrophy."

Prof Pat Kehoe from the University of Bristol, who led the trial, said: "It is vitally important we continue to search for effective treatments for AD because with an ageing population there will continue to be many people diagnosed with the disease, which will greatly impact on our already overstretched health and social care costs and resources."

The research was funded by the Efficacy and Mechanism Evaluation Programme (UK Medical Research Council and National Institute for Health Research).

Kehoe PG, Turner N, Howden B, Jarutyte L, Clegg SL, Malone IB, Barnes J, Nielsen C, Sudre CH, Wilson A, Thai NJ, Blair PS, Coulthard E, Lane JA, Passmore P, Taylor J, Mutsaerts HJ, Thomas DL, Fox NC, Wilkinson I, Ben-Shlomo Y. Safety and efficacy of losartan for the reduction of brain atrophy in clinically diagnosed Alzheimer's disease (the RADAR trial): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2021;20(11):895-906. doi: 10.1016/S1474-4422(21)00263-5. PMID: 34687634

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