Antihypertensive treatment guided by genetics: PEARL-HT, the randomized proof-of-concept trial comparing rostafuroxin with losartan
We compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension. Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutan...
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Published in | The pharmacogenomics journal Vol. 21; no. 3; pp. 346 - 358 |
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Main Authors | , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
01.06.2021
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | We compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension. Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutant α-adducin and of the ouabain-activated Na-K pump at 10
–11
M. Of 902 patients screened, 172 were enrolled in Italy and 107 in Taiwan. After stratification for country and genetic background, patients were randomized to rostafuroxin or losartan, being the difference in the fall in office systolic blood pressure (OSBP) after 2-month treatment the primary endpoint. Three pharmacogenomic profiles (P) were examined, considering: P1, adding to the gene variants included in the subsequent P2, the variants detected by post-hoc analysis of a previous trial; P2, variants of genes encoding enzymes for endogenous ouabain (EO) synthesis (
LSS
and
HSD3B1
), EO transport (
MDR1/ABCB1
), adducin (
ADD1
and
ADD3
); P3, variants of the
LSS
gene only. In Caucasians, the group differences (rostafuroxin 50 μg minus losartan 50 mg in OSBP mmHg) were significant both in P2 adjusted for genetic heterogeneity (P2a) and P3
LSS
rs2254524 AA [9.8 (0.6–19.0),
P
= 0.038 and 13.4 (25.4–2.5),
P
= 0.031, respectively]. In human H295R cells transfected with
LSS
A and
LSS
C variants, the EO production was greater in the former (
P
= 0.038); this difference was abolished by rostafuroxin at 10
–11
M. Chinese patients had a similar drop in OSBP to Caucasians with losartan but no change in OSBP with rostafuroxin. These results show that genetics may guide drug treatment for primary hypertension in Caucasians. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 ObjectType-News-3 content type line 23 |
ISSN: | 1470-269X 1473-1150 |
DOI: | 10.1038/s41397-021-00214-y |