Can losartan delay the progression of AD?

In individuals with clinically diagnosed mild-to-moderate Alzheimer’s disease (AD), treatment with the angiotensin II receptor blocker (ARB) losartan for 12 months did not reduce the rate of brain atrophy, findings from the phase II RADAR* trial suggest.

“[Given] the blood pressure (BP)-lowering function of losartan, it is possible that the drug might have some additional cerebrovascular benefits for patients with AD,” said the researchers. “[However, our findings do] not support evidence [showing] that ARBs might offer preferential benefit over other forms of hypertension treatment regarding the incidence and progression of AD.” [J Am Med Dir Assoc 2021;22:1386-1395.e15]

During the open-label phase, 261 participants who have not received prior ARBs were given losartan 25 mg QD for 7 days. Those keen on proceeding with the study took generic losartan 100 mg QD for 7 more days. If there were no contraindications, a washout phase ensued wherein participants received placebo for 4–14 days to ensure tolerance of the intervention, particularly in normotensive participants. A double-blind phase followed thereafter, comprising 211 participants who were randomized 1:1 to receive losartan or placebo (25 mg during the first 7 days; 100 mg from day 8 onwards) for 12 months. [Lancet Neurol 2021;20:895-906]

At 12 months, mean brain volume changes from baseline (as measured by BSI**) were similar between the losartan and the placebo arms (20.0 vs 19.1 mL; adjusted mean difference, 1.23 mL; p=0.41), as were the mean brain volumes (1,002 vs 1,018 mL; adjusted mean difference, –2.29 mL; p=0.14).

There were also no differences between losartan and placebo in terms of other cognitive parameters*** such as ADAS-Cog (23 vs 24; p=0.64), NPI (8 for both; p=0.30), MMSE (19 for both; p=0.56), DEMQOL (96 vs 94; p=0.74), DEMQOL-proxy (93 for both; p=0.33), and BADLS (10 vs 7; p=0.98), as well as in the volume of white matter hyperintensities in a subanalysis (11,992 vs 9,793; p=0.70).

Greater reductions in mean BP levels were seen with losartan vs placebo, both in terms of systolic (133 vs 139 mm Hg) and diastolic BP (78 vs 81 mm Hg; p<0.0001 for both), suggesting that “the intervention was biologically active”, noted the researchers.

“[However,] it is possible that losartan did not penetrate the blood-brain barrier as much as anticipated. Therefore, although peripherally active … it was not able to act more directly in the brain where it was intended to reduce disease-related atrophy,” they added.

The rates of serious adverse events (AEs) throughout the study period were similarly low between the losartan and placebo arms (n=20 in each arm). The most common serious AEs tied to losartan were infections (n=6) and mechanical injury (n=3).

Preclinical data have shown the ability of ARBs to prevent angiotensin II-mediated AD-like pathologies and reduce rates of cognitive decline. [J Alzheimers Dis 2018;62:1443-1466] “[These studies] highlight the potential involvement of angiotensin II in several pathological pathways in AD and frame our core hypothesis that pharmacological intervention against angiotensin II signalling by losartan might provide protection against multiple processes that cause the progression of AD brain pathology,” the researchers explained.

However, the findings failed to prove this hypothesis, underlining the importance of studies looking further into the capability of angiotensin II-lowering approaches in this setting. “[O]ther studies [have] yet to complete; [these] are also testing the angiotensin hypothesis of AD (ie, that excess angiotensin II signalling resulting from imbalance in the brain RAS^# contributes to the pathogenesis of AD) by investigating various ARBs in populations with no cognitive impairment but at risk of developing dementia,” said the researchers.

“Further research is needed to assess the potential therapeutic benefit from earlier treatment in patients with milder cognitive impairment or from longer treatment periods,” they added.