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Randomized Controlled Trial
. 2022 Dec 29;77(12):2356-2366.
doi: 10.1093/gerona/glac102.

Serum Concentrations of Losartan Metabolites Correlate With Improved Physical Function in a Pilot Study of Prefrail Older Adults

Jessica L Lee  1   2 , Cissy Zhang  3 , Reyhan Westbrook  1 , Mariann M Gabrawy  1 , Lolita Nidadavolu  1 , Huanle Yang  1 , Ruth Marx  1 , Yuqiong Wu  1 , Nicole M Anders  3   4 , Lina Ma  5 , Marcela-Dávalos Bichara  1 , Min-Ji Kwak  2 , Brian Buta  1 , Mohammed Khadeer  6 , Gayane Yenokyan  7 , Jing Tian  1 , Qian-Li Xue  1 , Helmy M Siragy  8 , Robert M Carey  8 , Rafael de Cabo  6 , Luigi Ferrucci  6 , Ruin Moaddel  6 , Michelle A Rudek  4   9 , Anne Le  4   10 , Jeremy D Walston  1 , Peter M Abadir  1
Affiliations
Randomized Controlled Trial

Serum Concentrations of Losartan Metabolites Correlate With Improved Physical Function in a Pilot Study of Prefrail Older Adults

Jessica L Lee et al. J Gerontol A Biol Sci Med Sci. .

Abstract

Losartan is an oral antihypertensive agent that is rapidly metabolized to EXP3174 (angiotensin-subtype-1-receptor blocker) and EXP3179 (peroxisome proliferator-activated receptor gamma [PPARγ] agonist), which was shown in animal studies to reduce inflammation, enhance mitochondrial energetics, and improve muscle repair and physical performance. We conducted an exploratory pilot study evaluating losartan treatment in prefrail older adults (age 70-90 years, N = 25). Participants were randomized to control (placebo) or treatment (daily oral losartan beginning at 25 mg per day and increasing every 8 weeks) for a total of 6 months. Fatigue, hyperkalemia, and hypotension were the most observed side effects of losartan treatment. Participants in the losartan group had an estimated 89% lower odds of frailty (95% confidence interval [CI]: 18% to 99% lower odds, p = .03), with a 0.3-point lower frailty score than the placebo group (95% CI: 0.01-0.5 lower odds, p = .04). Frailty score was also negatively associated with serum losartan and EXP3179 concentrations. For every one standard deviation increase in EXP3179 (ie, 0.0011 ng/μL, based on sample values above detection limit) and EXP3174 (ie, 0.27 ng/μL, based on sample values above detection limit), there was a 0.0035 N (95% CI: 0.0019-0.0051, p < .001) and a 0.0027 N (95% CI: 0.00054-0.0043, p = .007) increase in average knee strength, respectively.

Trial registration: ClinicalTrials.gov NCT01989793.

Keywords: Citric acid cycle; EXP3174; EXP3179; Frailty, Losartan.

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
Study design with participant enrollment, withdrawal, and completion.
Figure 2.
Figure 2.
Effects of losartan doses on the amino acid precursor metabolites that feed into the intermediate metabolites of the TCA cycle. Comparisons of the distributions of metabolites by losartan dose in the treatment group were conducted using Kruskal–Wallis one-way ANOVA with Dunn’s multiple comparisons test. *p < .05, **p < .01, and ***p < .005. TCA = tricarboxylic acid.
Figure 3.
Figure 3.
Effects of losartan doses on TCA cycle metabolites. Comparisons of the distributions of metabolites by losartan dose in the treatment group were conducted using Kruskal–Wallis one-way ANOVA with Dunn’s multiple comparisons test. *p < .05, **p < .01, and ***p < .005. TCA = tricarboxylic acid.
See this image and copyright information in PMC

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